JP6896715B2 - Heteroaryl derivative as sepiapterin reductase - Google Patents

Description

Heteroaryl derivative as sepiapterin reductase

Background Tetrahydrobiopterin (BH4) is an enzyme cofactor for various aromatic amino acid hydroxylases, including phenylalanine, tyrosine and tryptophan hydroxylase, and other enzymes such as nitric oxide synthase (inducible NOS (iNOS)). , Endophilic NOS (eNOS), Neuron NOS (nNOS)), and important cofactors for alkylglycerol monooxygenase. Thus, BH4 is involved in the regulation of the production of various neurotransmitters (eg serotonin and dopamine) and nitric oxide. BH4 deficiency is associated with a deficiency of neurotransmitters, including serotonin and dopamine. Decreased BH4 production is also associated with decreased pain sensitivity after injury.

The final step in the new pathway for BH4 biosynthesis is the conversion of 6-pyrvoyl tetrahydropterin to BH4 by the action of sepiapterin reductase. Sepiapterin reductase (SPR) is inhibited by the clinically approved drug sulfasalazine and other sulfa drugs, thereby interfering with the novel biosynthesis of BH4.

Summary Compounds of formulas I, I', II, II', III, III', IV, IV', V and V'and pharmaceutically acceptable salts thereof are disclosed herein.

Compositions (eg, pharmaceutical compositions) comprising one or more of the compounds disclosed herein and a pharmaceutically acceptable carrier are also disclosed.

Further disclosed are methods of using one or more compounds disclosed herein, or pharmaceutical compositions thereof. The methods include methods of inhibiting sepiapterin reductase (SPR), treating subjects suffering from pain, treating subjects suffering from inflammation, and / or immunological disorders. Includes methods of treating affected subjects.

These and other embodiments and features of the invention will become apparent from the detailed description of the preferred embodiments below.

Detailed Description The use of sepiapterin reductase (SPR) inhibitors and sepiapterin reductase inhibitors in the treatment of analgesia, acute and chronic pain, anti-inflammatory and immune cell regulation is disclosed herein. To. In a mouse model, administration of SPR inhibitors reduced pain hypersensitivity and BH4 levels in target tissues (Latremoriere et al., Neuron, 86: 1393-1406 (2015)).

The use of the terms "a", "an", "the" and similar referents in the context of describing the invention (particularly in the claims) is both singular and plural, unless otherwise noted. Should be interpreted as including. The enumeration of the range of values herein is intended to serve as a simplification to individually reference each distinct value within the range, unless otherwise indicated herein. The value of is incorporated into the specification, as described individually in the specification. The use of any and all examples, or exemplary terms (eg, "etc.") provided herein is intended to better illustrate the invention and is not otherwise asserted. As long as it is not limited, the scope of the present invention is not limited. Nothing in the specification should be construed as indicating an unclaimed element essential to the practice of the present invention.

As used herein, the term "alkyl" refers to a linear or branched hydrocarbon group, including, but not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t. -Butyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, n-hexyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,2-dimethylbutyl, 2, Includes 3-dimethylbutyl, 3,3-dimethylbutyl, and 2-ethylbutyl. The term C _mn means that the alkyl group has "m" to "n" carbon atoms. The term "alkylene" refers to an alkyl group having a substituent. Alkyl (e.g., methyl) or alkylene (e.g., -CH 2 _-) group, such as halo independently selected, trifluoromethyl, trifluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or amino It can be replaced by one or more of the groups, typically 1-3.

As used herein, the term "halo" refers to fluoro, chloro, bromo and iodine. The term "hydroxy" is defined as -OH. The term "alkoxy" is defined as -OR where R is alkyl. The term "amino" is _{defined as -NH 2} and the term "alkylamino" is _{defined as -NR 2} , where at least one R is alkyl and the second R is alkyl or hydrogen. The term "carbamoyl" is defined as _{-C (= O) NR 2.} The term "carboxy" is defined as -C (= O) OH or a salt thereof. The term "nitro" is defined as _{-NO 2.} The term "cyano" is defined as -CN. The term "trifluoromethyl" is defined as _{-CF 3.} The term "trifluoromethoxy" is defined as _{-OCF 3.}

As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic group, preferably a monocyclic or bicyclic aromatic group. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthryl, phenanthryl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic and tricyclic carbocycles in which one ring is aromatic and the other is saturated, partially unsaturated or aromatic, such as dihydronaphthyl, indenyl, indanyl or tetrahydronaphthyl (tetralinyl). .. Unless otherwise stated, aryl groups are unsubstituted or, for example, halo, alkyl, alkenyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amino, alkylamino, -CO ₂ It can be substituted with one or more individually selected from H, -CO ₂ alkyl, -OCO alkyl, aryl and heteroaryl, in particular 1 to 4 substituents.

The term "benzyl" as used herein _{refers to -CH 2} -phenyl. Unless otherwise indicated, the benzyl group is unsubstituted or, for example, halo, alkyl, alkenyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amino, alkylamino, -CO. ₂ H, -CO ₂ alkyl, --OCO alkyl, aryl and one or more selected independently from heteroaryl, may be particularly substituted with 1 to 4 substituents.

As used herein, the term "heterocyclic" refers to a heteroaryl or heterocycloalkyl ring system. As used herein, the term "carbon ring" refers to an aryl or cycloalkyl ring system.

As used herein, the term "heteroaryl" is a monocyclic or polycyclic ring containing one or two aromatic rings, the aromatic ring containing at least one nitrogen, oxygen or sulfur atom. It refers to a system (for example, a bicyclic system). Each ring of the heteroaryl group can contain one or two O atoms, one or two S atoms, and / or one to four N atoms, but of the heteroatom of each ring. The total number is 4 or less, and each ring contains at least one carbon atom. In certain embodiments, the heteroaryl group has 5-20, 5-15, or 5-10 ring atoms. Examples of monocyclic heteroaryl groups include flanyl, imidazolyl, isothiazolyl, isooxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridadinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl and triazolyl. , Not limited to these. Examples of bicyclic heteroaryl groups include benzofuranyl, benzoimidazolyl, benzoisoxazolyl, benzopyranyl, benzothiasiazolyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzotriazolyl, benzoxazolyl, flopyridyl, imidazole. Pyrizinyl, imidazoliazolyl, indolidinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindrill, isoquinolinyl, isothiazolyl, naphthylidine, oxazolopyridinyl, phthalazinyl, pteridinyl, prynyl, pyridopyridyl, pyropyridyl, quinolinyl, Examples include, but are not limited to, quinoxalinyl, chiazolinyl, thiadiazolopyrimidyl and thienopyridyl. Unless otherwise indicated, heteroaryl groups are unsubstituted or, for example, halo, alkyl, alkenyl, -OCF ₃ , -NO ₂ , -CN, -NC, -OH, alkoxy, amino, alkylamino,-. CO ₂ H, -CO ₂ alkyl, --OCO alkyl, aryl, and one or more selected from heteroaryl, may be particularly substituted with 1 to 4 substituents.

As used herein, the term "cycloalkyl" means monocyclic or polycyclic (eg, bicyclic), saturated or partially unsaturated ring systems, which are three or more carbon atoms. Containing (3-12, or 3-8) and containing cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl, optionally, eg, individually selected halos, tolylomethyls, tris. It is optionally substituted with one or more, typically 1-3, fluoromethoxy, hydroxy, alkoxy, nitro, cyano, alkylamino, or amino groups.

As used herein, the term "heterocycloalkyl" is monocyclic or polycyclic (eg, bicyclic), saturated or partially containing 3 or more (eg, 4-12) total atoms. It means an unsaturated ring system, of which 1 to 5 atoms are selected independently of nitrogen, oxygen and sulfur, and the remaining atoms are carbon. Non-limiting examples of heterocycloalkyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dihydropyrrolill, morpholinyl, thiomorpholinyl, dihydropyridinyl, oxacycloheptyl, dioxacycloheptyl, thiacycloheptyl, diazacycloheptyl. _{Halo, C 1-6} alkyl, C _1-6 alkoxy, cyano, amino, carbamoyl, nitro, carboxy, C _2-7 alkenyl, C _2-7 alkynyl, etc., each of which is arbitrarily and independently selected. One or more, typically 1-3, are substituted on the atoms of the ring.

The compounds disclosed herein include all pharmaceutically acceptable isotope-labeled compounds, wherein one or more atoms of the compounds disclosed herein have the same atomic number. with, but the atomic mass or mass number usually found in nature are replaced by an atom having a different atomic mass or mass number, this specific example, isotopes of hydrogen, such as ^{2 H,} 3 ^H and the like. In some cases, one or more hydrogen atoms of the compounds disclosed herein are specifically ² H (deuterium). The isotope-labeled compounds disclosed herein generally include schemes and attachments that use suitable isotope-labeled reagents by conventional techniques known to those of skill in the art or in place of pre-used unlabeled reagents. It can generally be prepared by a method similar to that described in the examples.

The particular compounds disclosed herein exist as stereoisomers (ie, isomers that differ only in the spatial arrangement of atoms), including optical isomers and conformational isomers (or conformational isomers). obtain. The compounds disclosed herein are all stereoisomers as both pure individual stereoisomer preparations and their respective concentrated preparations, as well as racemic mixtures of such stereoisomers and those skilled in the art. Includes both individual diastereomers and enantiomers that can be separated according to known methods. In addition, the compounds disclosed herein include all tautomeric forms of the compounds.

ＺはＣＲ^１又はＮＲ^１であり、又は二重結合が存在する場合、ＺはＣＲ^１又はＮであり；
ＹがＮＲ^２又はＣＲ^２であるか、又は二重結合が存在する場合、ＹはＮ又はＣＲ^２であり；
ＸはＮ又はＣＲ^５ａであり；
Ｒ^１及びＲ^２は、それらが結合している原子と一緒になって、４、５、６又は７員環を形成し；又は
Ｒ^１及びＲ^２は、Ｈ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、Ｃ_１−５ハロアルキル、及びハロからなる群から独立して選択され；
Ｒ^５及びＲ^５ａは、Ｈ及びＣ_１−５アルキルからなる群から独立して選択され；
Ｌは、ヘテロアリール−Ｃ_０−５アルキレン−、アリール−Ｃ_０−５アルキレン−、−Ｓ−Ｃ_１−５アルキレン−アリール、−Ｓ−Ｃ_１−５アルキレン−ヘテロアリール、−Ｃ_１−５アルキレン−Ｓ−アリール、又は−Ｃ_１−５アルキレン−Ｓ−ヘテロアリールであり；
Ｒ^３及びＲ^４は、それらが結合している窒素原子と一緒になって、３、４、５、６又は７員単環又は６、７、８、９、１０、１１、１２、１３又は１４員のスピロ環、縮合環及び／又は架橋多環式（例えば、二環式）環を形成し；又は
Ｒ^３は、Ｈ、Ｃ_１−５アルキル、Ｃ_３−１０シクロアルキル、Ｃ_１−５ハロアルキル、アリール、ヘテロアリール、及びＣ_１−５アルキレン−Ｇからなる群より選択され、
Ｒ^４は、Ｃ_１−５アルキル、Ｃ_３−１０シクロアルキル、Ｃ_１−５ハロアルキル、アリール、ヘテロアリール、及びＣ_１−５アルキレン−Ｇからなる群から選択され；及び
各Ｇは、独立して、ＣＮ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルからなる群から選択される。 In one aspect, the disclosure provides a compound of formula I or I', or a pharmaceutically acceptable salt thereof:

Z is CR ¹ or NR ¹ , or if a double bond is present, Z is CR ¹ or N;
If Y is NR ² or CR ² , or if a double bond is present, then Y is N or CR ² ;
X is N or CR ^5a ;
R ¹ and R ² together with the atoms to which they are attached form a 4, 5, 6 or 7-membered ring; or R ¹ and R ² are H, C _1-5 alkyl, C. Selected independently from the group consisting of _3-5 cycloalkyl, C _{1-5 haloalkyl, and halo;}
R ⁵ and R ^5a were independently selected from the group consisting of H and C _{1-5 alkyl;}
L is heteroaryl-C _0-5 alkylene-, aryl-C _0-5 alkylene- _{, -SC 1-5} alkylene-aryl, -SC _1-5 alkylene-heteroaryl, -C _1-5. It is alkylene-S-aryl, or -C _1-5 alkylene-S-heteroaryl;
R ³ and ^{R 4,} together with the nitrogen atom to which they are attached, 3, 4, 5, 6 or 7-membered monocyclic or 6,7,8,9,10,11,12,13 or Forming 14-membered spiro rings, fused rings and / or crosslinked polycyclic (eg, bicyclic) rings; or R ³ is H, C _1-5 alkyl, C _3-10 cycloalkyl, C _1- Selected from the group consisting of ₅ haloalkyl, aryl, heteroaryl, and C _{1-5 alkylene-G.}
R ⁴ is _{selected from the group consisting of C 1-5} alkyl, C _3-10 cycloalkyl, C _1-5 haloalkyl, aryl, heteroaryl, and C _1-5 alkylene-G; and each G is independent. It is selected from the group consisting of CN, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

In some embodiments, the compounds of formula I do not include compounds having the structures listed in Table 4 (Table D) below.

ここで：
ＹがＮＲ^２又はＣＲ^２であるか、又は二重結合が存在する場合、ＹはＣＲ^２であり；そして
Ｒ^１及びＲ^２は、それらが結合している原子と一緒になって、４、５、６、又は７員環を形成する。 In some embodiments, the present disclosure provides compounds having the formula IA or IA':

here:
If Y is NR ² or CR ² , or if a double bond is present, then Y is CR ² ; and R ¹ and R ² together with the atoms to which they are bonded 4, Form a 5, 6 or 7 membered ring.

式ＩＡ又はＩＡ’の化合物には、これらに限定されるものではないが、以下の構造を有する化合物をも含む：

Compounds of formula IA or IA'are not limited to, but are limited to.
Including compounds having a structure selected from the group consisting of:

Compounds of formula IA or IA'including, but are not limited to, compounds having the following structures:

In some embodiments, R ¹ and R ² together with the atoms to which they are attached form a heteroaryl ring, aryl ring, heterocycloalkyl ring, or cycloalkyl ring. In some embodiments, R ¹ and R ^2, together with the atoms to which they are attached, pyrrole ring, a cyclopentene ring, a thiophene ring, dihydrofuran ring, a cyclohexene ring, a pyrazole ring, a thiazole ring, a benzene It forms a ring, an imidazole ring, or a cyclobutene ring.

ここでＲ^１及びＲ^２は、Ｈ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、Ｃ_１−５ハロアルキル、及びハロからなる群から独立して選択される。 In some embodiments, the present disclosure provides compounds having the formula IB or IB':

Here, R ¹ and R ² are independently selected from the group consisting of H, C _1-5 alkyl, C _3-5 cycloalkyl, C _{1-5 haloalkyl, and halo.}

は、下記からなる群から選択される：

場合によっては、

は、

である。
場合によっては、

は、

であり、又は

は、

である。 In some embodiments,

Is selected from the group consisting of:

In some cases,

Is

Is.
In some cases,

Is

Or

Is

Is.

In some embodiments, L is, _{-S-C 1-5} alkylene - aryl, _{-S-C 1-5} alkylene - _{heteroaryl, -C 1-5} alkylene -S- aryl, or _{-C 1-5} It is an alkylene-S-heteroaryl. In other embodiments, L is aryl-C _1-5 alkylene- or heteroaryl-C _1-5 alkylene-. In yet another embodiment, L is a heteroaryl or aryl, such as, but not limited to, a 5- or 6-membered heteroaryl ring. Suitable L groups include, but are not limited to, pyrazolyl, triazolyl, thiazolyl, pyridinyl, imidazolyl, phenyl, thiophenyl, pyrrolyl and indolyl.

であり；
ｎは０又は１であり；
ＱはＣＨ、ＣＲ^６又はＮであり；
各Ｒ^６は、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、ハロ、ベンジル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^１１、−ＮＲ^１１ＣＯ_２Ｒ^１１ａ、−ＳＯ_２Ｒ^１１、−ＳＯ_２ＮＨＲ^１１、−ＳＯＲ^１１、−ＣＯ_２Ｒ^１１、−ＣＯＮＨＲ^１１、アリール、及びヘテロアリールからなる群から選択され；及び
Ｒ^１１及びＲ^１１ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、Ｃ_１−５ハロアルキル、−Ｃ_０−５アルキレン−Ｃ_３−６シクロアルキル、−Ｃ_０−５アルキレン−ヘテロシクロアルキル、−Ｃ_０−５アルキレン−アリール、及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択される。場合によっては、

は、

である。 In some embodiments, L is

Is;
n is 0 or 1;
Q is CH, CR ⁶ or N;
Each R ⁶ is C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, halo, benzyl, C _1-5 haloalkylene-OH, C _1-5 alkylene-CN, C. _1-5 Alkoxy, C _1-5 Haloalkoxy, Aryloxy, Heteroaryloxy, CN, OH, -NHR ¹¹ , -NR ¹¹ CO ₂ R ^11a , -SO ₂ R ¹¹ , -SO ₂ NHR ¹¹ , -SOR ¹¹ , -CO ₂ R ¹¹ , -CONHR ¹¹ , aryl, and heteroaryl; and R ¹¹ and R ^11a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, respectively. Selected from the group consisting of -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl.} To. In some cases,

Is

Is.

であり；
ｎは０、１又は２であり；
各Ｒ^６は、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、ハロ、ベンジル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^１１、−ＮＲ^１１ＣＯ_２Ｒ^１１ａ、−ＳＯ_２Ｒ^１１、−ＳＯ_２ＮＨＲ^１１、−ＳＯＲ^１１、−ＣＯ_２Ｒ^１１、−ＣＯＮＨＲ^１１、アリール、及びヘテロアリールからなる群から選択され；及び
Ｒ^１１及びＲ^１１ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、Ｃ_１−５ハロアルキル、−Ｃ_０−５アルキレン−Ｃ_３−６シクロアルキル、−Ｃ_０−５アルキレン−ヘテロシクロアルキル、−Ｃ_０−５アルキレン−アリール、及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択される。適切なＬ基には、これに限定されるものではないが、

が含まれる。 In some embodiments, L is

Is;
n is 0, 1 or 2;
Each R ⁶ is C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, halo, benzyl, C _1-5 haloalkylene-OH, C _1-5 alkylene-CN, C. _1-5 Alkoxy, C _1-5 Haloalkoxy, Aryloxy, Heteroaryloxy, CN, OH, -NHR ¹¹ , -NR ¹¹ CO ₂ R ^11a , -SO ₂ R ¹¹ , -SO ₂ NHR ¹¹ , -SOR ¹¹ , -CO ₂ R ¹¹ , -CONHR ¹¹ , aryl, and heteroaryl; and R ¹¹ and R ^11a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, respectively. Selected from the group consisting of -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl.} To. Suitable L groups are, but are not limited to,

Is included.

から選択される構造を有し、かつ、
０、１、又は２個のＲ^６置換基で置換される。
場合によっては、Ｌは以下からなる群から選択される。

場合によっては、Ｌは

である。 In some embodiments, L is

Has a structure selected from
0,1, or is substituted with two ^{R 6} substituents.
In some cases, L is selected from the group consisting of:

In some cases, L is

Is.

から選択された構造を有し、かつＣＨ_２Ｄ、ＣＨＤ_２又はＣＤ_３などの１又は２重水素Ｃ_１−５アルキル置換基で置換されている。場合によっては、Ｌは、

から選択された構造を有する。 Optionally, one or more hydrogen atoms of L groups disclosed herein is substituted with ^{2 H} (deuterium). In some cases, L is

It has a structure selected from, and _CH 2 D, is substituted with 1 or 2 deuterium _{C 1-5} alkyl substituents, such as CHD ₂ or CD _3. In some cases, L is

Has a structure selected from.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered ring, including but not limited to piperidinyl. , Pyrrolidinyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, oxadiridinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, azepanyl, diazepanyl or diazabicyclohep.

は、

であり；
ｍは０、１、２又は３であり；
Ｒ^７及びＲ^９は、それぞれ独立して、ハロ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^８、−ＮＲ^８ＣＯ_２Ｒ^８ａ、−ＳＯ_２Ｒ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＨＲ^８、アリール、及びヘテロアリールからなる群から選択され、又は
２個のＲ^７基はそれらが結合している炭素原子と一緒になって、３、４、５、６、７又は８員のシクロアルキル、３、４、５、６、７又は８員のヘテロシクロアルキル、アリール、又は５もしくは６員のヘテロアリール環を形成し；及び
Ｒ^８及びＲ^８ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、Ｃ_１−５ハロアルキル、−Ｃ_０−５アルキレン−Ｃ_３−６シクロアルキル、−Ｃ_０−５アルキレン−ヘテロシクロアルキル、−Ｃ_０−５アルキレン−アリール及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択され；又は
１個のＲ^７基及びＲ^９は、それらが結合している原子と一緒になって５又は６員のヘテロシクロアルキル又はヘテロアリール環を形成する。 In some embodiments,

Is

Is;
m is 0, 1, 2 or 3;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _{1-5, respectively.} Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^8, -CONHR ^8, aryl, and heteroaryl, or two ^{R 7} groups taken together with the carbon atoms to which they are attached, 3,4,5,6,7 or 8-membered cycloalkyl, 5, 6, 7 or 8 membered heterocycloalkyl, aryl, or 5 or to form a 6-membered heteroaryl ring; and R ⁸ and ^{R 8a} are each independently , H, C _1-5 alkyl, C _1-5 haloalkyl, -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl and- Selected from the group consisting of C _0-5 alkylene-heteroaryl; or one R ⁷ group and R ⁹ together with the atom to which they are attached are 5 or 6 membered heterocycloalkyl or heteroaryl. Form a ring.

は、

であり；
Ｒ^７及びＲ^９は、それぞれ独立して、ハロ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^８、−ＮＲ^８ＣＯ_２Ｒ^８ａ、−ＳＯ_２Ｒ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＨＲ^８、アリール、及びヘテロアリールからなる群から選択され；及び
Ｒ^８及びＲ^８ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、Ｃ_１−５ハロアルキル、−Ｃ_０−５アルキレン−Ｃ_３−６シクロアルキル、−Ｃ_０−５アルキレン−ヘテロシクロアルキル、−Ｃ_０−５アルキレン−アリール及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択される。 In some embodiments,

Is

Is;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _1-5. Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^{Selected from the group consisting of 8} , -CONHR ⁸ , aryl, and heteroaryl; and R ⁸ and R ^8a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, -C _{0-5, respectively.} It is selected from the group consisting of alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl and -C _{0-5 alkylene-heteroaryl.}

In some embodiments, R ⁷ or R ⁹ is _{selected from the group consisting of C 3-5} cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, aryl and heteroaryl. In some embodiments, R ⁷ is oxazolyl or pyridinyl, each optionally substituted with CN or F. In some embodiments, R ⁷ is selected from the group consisting of:

In some embodiments, R ⁹ is C _3-5 cycloalkyl. In some embodiments, R ⁹ is cyclopropyl or cyclobutyl, each optionally substituted with 1, 2, 3 or 4 F atoms. In some embodiments, R ⁹ is selected from the group consisting of:

は、

である。 In some embodiments,

Is

Is.

は、

であり；及び２つのＲ^７基が隣接する炭素原子上に存在し、いくつかの場合において、場合によっては、２つのＲ^７基は、４、５、６又は７員ヘテロ環式基又は炭素環式基をそれらが結合している炭素原子と一緒に形成する。いくつかの実施形態では、

は、

であり；及び
２つのＲ^７基は、同じ炭素原子上に存在し、場合によっては、この２つのＲ^７基は、３、４、５、６又は７員のヘテロシクロアルキル基又はシクロアルキル基を、それらが結合している炭素原子と一緒に形成する。 In some embodiments,

Is

In it; and present on the two carbon atoms to which R ⁷ groups are adjacent, in some cases, in some cases, the two R ⁷ groups, 4, 5, 6 or 7-membered heterocyclic group or C Cyclic groups are formed with the carbon atoms to which they are attached. In some embodiments,

Is

In it; and the two R ⁷ groups are present on the same carbon atom, in some cases, the two R ⁷ groups, 3, 4, 5, 6 or 7-membered heterocycloalkyl or cycloalkyl group Form together with the carbon atoms to which they are attached.

In some embodiments, at least one R ⁷ or R ⁹ is F, CF ₃ , CH ₃ , CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, 1-cyano-cyclopropyl, CN, -C. (CH ₃ ) ₂ CN, -CH (CN) CH ₂ CH ₃ , 3, 3-difluoropyrrolidin, -OH, -OCH ₃ , OCH ₂ CH ₃ , -OCH ₂ CF ₃ , -C (OH) (CF ₃₎ ) ₂ , -C (OH) CH ₃ CF ₃ , -CO ₂ C (CH ₃ ) ₃ , -CONHC (CH ₃ ) ₃ , -N (CH ₃ ) CO ₂ C (CH ₃ ) ₃ , Phenoxy, Phenylsulfonyl , 3,4-difluoro-benzenesulfonyl, phenyl, fluorophenyl, difluorophenyl, cyanophenyl, indolyl, or difluoromethoxy pyrrolidinylmethyl or benzothiazolyl, or two R ⁷ groups, and the carbon atom to which they are attached Together they form a fused benzene ring. In some embodiments, at least one R ⁷ is 3-indrill, 6-fluoro-3-indrill, N-methyl-3-indrill, 4-indrill, 2-benzothiazolyl or 5-fluoro-2-benzothiazolyl. is there.

In some embodiments, R ⁹ is -C _0-5 alkylene-aryl. In some embodiments, R ⁹ is 2,4-difluorophenyl, 5-fluorophenyl, phenyl or 2-chlorophenyl.

In some embodiments, ^{R 3} and ^{R 4} together with the nitrogen atom to which they are attached, 6,7,8,9,10,11,12,13 or 14-membered spiro ring, A fused ring or a crosslinked polycyclic (eg, bicyclic) ring is formed. Suitable 6-14 member spiro rings, fused rings or crosslinked bicyclic rings include 10-azabicyclodecane, 9-azabicyclononane, 8-azabicyclooctane (eg 8-azabicyclo [3.2.1]). Octane), azabicycloheptan (eg 7-azabicycloheptan), 3-azabicyclohexane (eg 3-azabicyclo [3.1.0] hexane), diazabicyclononane (eg 1,4-diazabicyclo [4] .3.0] Nonan), diazabicyclooctane, diazabicycloheptan, diazaspirononan, azaspirononan, diazaspirooctane, azaspirooctane, spiro [isobenzofuran-piperidin, diazaspiroheptane, azaspiroheptane, Includes, but is not limited to, octahydrocyclopenta [b] pyrol, or octahydrocyclopenta [c] pyrol. In some embodiments, the 6-14 member spiro, fused or crosslinked polycyclic (eg, bicyclic) rings are independently halo, C _1-5 alkyl, C _1-5 haloalkyl, C, respectively. _{Select from the group consisting of 1-5} alkoxy, aryloxy, heteroaryloxy, CN, OH, -SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , -CONHR ¹⁰ , C _3-5 cycloalkyl, oxo, aryl and heteroaryl. Substituents are substituted with one or two substituents; and R ¹⁰ consists of the group consisting of H, C _1-5 alkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl.} Be selected. In some embodiments, at least one substituent of a 6-14 member spiro ring, fused ring, or crosslinked polycyclic (eg, bicyclic) ring is cyclopropyl, F, -CO ₂ C (CH). ₃ ) ₃ , -CH ₂ CF ₃ , CF ₃ , fluorophenyl, cyanophenyl, OH, or phenyl.

からなる群から選択される。 In some embodiments, R ³ is H, CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH (CH ₃ ) ₂ , -CH ₂ CF ₃ , -CH ₂ CH ₂ CN. , -CH ₂ CH (OH) CF ₃ and selected from the group consisting of benzyl; and R ⁴ are CH ₃ , -CH ₂ CH ₃ , -CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ CF ₃ ,-. CH ₂ CF ₂ CF ₃ , cyclohexyl, cyclopentyl, benzyl,

Selected from the group consisting of.

は、

である。 In some embodiments

Is

Is.

基は、これらに限定されるものではないが、以下の化合物をも含む。

Appropriate,

The group also includes, but is not limited to, the following compounds.

Exemplary compounds of formula I include, but are not limited to, the compounds listed in Table 1 (Table A).

Exemplary compounds of formula I also include, but are not limited to, the compounds listed in Table 2 (Table B).

The compounds disclosed herein are provided in Table 3 (Table C):

ここで、Ｌがヘテロアリール又はアリールであり；及び
Ｒ^３は、Ｈ、Ｃ_１−５アルキル、Ｃ_３−１０シクロアルキル、Ｃ_１−５ハロアルキル、アリール、ヘテロアリール、及びＣ_１−５アルキレン−Ｇからなる群から選択され；
Ｒ^４は、Ｃ_１−５アルキル、Ｃ_３−１０シクロアルキル、Ｃ_１−５ハロアルキル、アリール、ヘテロアリール、及びＣ_１−５アルキレン−Ｇからなる群から選択され；又は
Ｒ^３及びＲ^４は、それらが結合している窒素原子と一緒になって、３、４、５、６又は７員の単環式環、又は６、７、８、９、１０、１１、１２、１３又は１４員のスピロ環、縮合環又は架橋二環式環を形成し、及び
各Ｇは、独立して、ＣＮ、アリール、ヘテロアリール、シクロアルキル、及びヘテロシクロアルキルからなる群から選択される。 In one aspect, the disclosure provides a compound of formula II or II'or a pharmaceutically acceptable salt thereof:

Where L is heteroaryl or aryl; and R ³ is H, C _1-5 alkyl, C _3-10 cycloalkyl, C _1-5 haloalkyl, aryl, heteroaryl, and C _1-5 alkylene-. Selected from the group consisting of G;
R ⁴ is selected from the group consisting of _{C 1-5} alkyl, C _3-10 cycloalkyl, C _1-5 haloalkyl, aryl, heteroaryl, and C _1-5 ^{alkylene-G; or R 3} and R ⁴ are , 3, 4, 5, 6 or 7-membered monocyclic rings, or 6, 7, 8, 9, 10, 11, 12, 13 or 14-membered, together with the nitrogen atoms to which they are attached. A spiro ring, a fused ring or a crosslinked bicyclic ring is formed, and each G is independently selected from the group consisting of CN, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl.

ＺはＣＲ^１又はＮＲ^１であり、又は二重結合が存在する場合、ＺはＣＲ^１又はＮであり；
ＹはＣＲ^２又はＮＲ^２であり、又は二重結合が存在する場合、ＹはＣＲ^２又はＮであり；
ＸはＣＨ又はＮであり；
Ｒ^１及びＲ^２は、Ｈ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、Ｃ_１−５ハロアルキル、及びハロからなる群から独立して選択される；又は
Ｒ^１及びＲ^２は、それらが結合している原子と一緒になって、５〜６員環を形成し；
Ｒ^５は、Ｈ及びＣ_１−５アルキルからなる群から選択され；
Ｌは、ヘテロアリール−Ｃ_０−５アルキレン−、アリール−Ｃ_０−５アルキレン−、−Ｓ−Ｃ_１−５アルキレン−アリール、−Ｓ−Ｃ_１−５アルキレン−ヘテロアリール、−Ｃ_１−５アルキレン−Ｓ−アリール、又は−Ｃ_１−５アルキレン−Ｓ−ヘテロアリールであり；
Ａは、以下の群から選択される。

In one aspect, the disclosure provides a compound of formula III or III', or a pharmaceutically acceptable salt thereof:

Z is CR ¹ or NR ¹ , or if a double bond is present, Z is CR ¹ or N;
Y is CR ² or NR ² , or if a double bond is present, Y is CR ² or N;
X is CH or N;
R ¹ and R ² are independently selected from the group consisting of H, C _1-5 alkyl, C _3-5 cycloalkyl, C _1-5 ^{haloalkyl, and halo; or R 1} and R ² are them. Together with the atoms to which they are bonded, they form a 5- to 6-membered ring;
R ⁵ is selected from the group consisting of H and C _{1-5 alkyl;}
L is heteroaryl-C _0-5 alkylene-, aryl-C _0-5 alkylene- _{, -SC 1-5} alkylene-aryl, -SC _1-5 alkylene-heteroaryl, -C _1-5. It is alkylene-S-aryl, or -C _1-5 alkylene-S-heteroaryl;
A is selected from the following groups.

In some embodiments, the compound of formula III or III'does not include a compound having the following structure:

ＹがＮＲ^２であるか、又は二重結合が存在する場合、ＹはＣＲ^２であり；
Ｒ^１及びＲ^２は、それらが結合している原子と一緒になって、５員環を形成し；
ｎは０又は１であり；
各Ｒ^６は、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、Ｃ_１−５ハロアルキル、ハロ、及びベンジルからなる群から選択され；
ＱはＣＨ、ＣＲ^６又はＮであり；
Ｒ^３及びＲ^４は、それらが結合している窒素原子と一緒になって、３、４、５、６又は７員単環式環又は６、７、８、９、１０、１１、１２、１３又は１４員のスピロ環、縮合環又は架橋二環式環を形成する。 In one aspect, the disclosure provides a compound of formula IV or IV', or a pharmaceutically acceptable salt thereof:

If Y is NR ² or a double bond is present, then Y is CR ² ;
R ¹ and R ² together with the atoms to which they are attached form a 5-membered ring;
n is 0 or 1;
Each R ⁶ is _{selected from the group consisting of C 1-5} alkyl, C _3-5 cycloalkyl, C _1-5 haloalkyl, halo, and benzyl;
Q is CH, CR ⁶ or N;
R ³ and R ⁴ together with the nitrogen atom to which they are attached are 3, 4, 5, 6 or 7-membered monocyclic rings or 6, 7, 8, 9, 10, 11, 12, It forms a 13- or 14-membered spiro ring, fused ring or crosslinked bicyclic ring.

であり、
ｍは０、１、２又は３であり；
Ｒ^７及びＲ^９は、それぞれ独立して、ハロ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^８、−ＮＲ^８ＣＯ_２Ｒ^８ａ、−ＳＯ_２Ｒ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＨＲ^８、アリール、及びヘテロアリールからなる群から選択され、又は
２個のＲ^７基はそれらが結合している炭素原子と一緒になって、３、４、５、６、７又は８員のシクロアルキル、３、４、５、６、７又は８員のヘテロシクロアルキル、アリール、又は５もしくは６員のヘテロアリール環を形成し；及び
Ｒ^８及びＲ^８ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、Ｃ_１−５ハロアルキル、−Ｃ_０−５アルキレン−Ｃ_３−６シクロアルキル、−Ｃ_０−５アルキレン−ヘテロシクロアルキル、−Ｃ_０−５アルキレン−アリール及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択され；又は
１個のＲ^７基及びＲ^９は、それらが結合している原子と一緒になって５又は６員のヘテロシクロアルキル又はヘテロアリール環を形成する。 In some embodiments

And
m is 0, 1, 2 or 3;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _{1-5, respectively.} Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^8, -CONHR ^8, aryl, and heteroaryl, or two ^{R 7} groups taken together with the carbon atoms to which they are attached, 3,4,5,6,7 or 8-membered cycloalkyl, 5, 6, 7 or 8 membered heterocycloalkyl, aryl, or 5 or to form a 6-membered heteroaryl ring; and R ⁸ and ^{R 8a} are each independently , H, C _1-5 alkyl, C _1-5 haloalkyl, -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl and- Selected from the group consisting of C _0-5 alkylene-heteroaryl; or one R ⁷ group and R ⁹ together with the atom to which they are attached are 5 or 6 membered heterocycloalkyl or heteroaryl. Form a ring.

であり、及び任意に、Ｆ、Ｃｌ及びＣ_１−３アルキルからなる群から選択される１〜４の置換基で置換される。 In some embodiments,

And optionally be substituted with 1-4 substituents selected from the group consisting of F, Cl and C _{1-3 alkyl.}

である。 In some embodiments,

Is.

In some embodiments, present on the carbon atom to which the two R ⁷ groups are adjacent, in some cases, the carbon group two of R ⁷ and which they are attached are 3, 4, 5, 6 or 7 Form a member heterocycloalkyl group or cycloalkyl group. In some embodiments, the two R ⁷ groups are present on the same carbon atom, in some cases, together with the carbon to which group the two R ⁷ and which they are attached, 3, 4, 5, 6 or 7-membered To form a heterocycloalkyl or cycloalkyl group. In some embodiments, the 6-14 member spiro ring, fused ring, or crosslinked polycyclic (eg, bicyclic) ring is independently halo, C _1-5 alkyl, C _1-5. From the group consisting of haloalkyl, C _1-5 alkoxy, aryloxy, heteroaryloxy, CN, OH, -SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , -CONHR ¹⁰ , C _3-5 cycloalkyl, aryl and heteroaryl. Substituent with one or two substituents of choice; and this R ¹⁰ is selected from the group consisting of H, C _1-5 alkyl, -C _0-5 alkylene-aryl and C _{0-5 alkylene-heteroaryl.} Will be done. In some embodiments, the 3-, 4-, 5-, 6- or 7-membered heterocycloalkyl or cycloalkyl groups are fluoro, hydroxy, cyano, methyl, ethyl, trifluoromethyl, trifluoroethyl, Cyanopropyl, methoxy, trifluoromethoxy, trifluoroethoxy, hexafluorohydroxypropyl, cyclopropyl, 1-cyano-cyclopropyl, 1-trifluoromethylcyclopropyl, 3,3-difluoropyrrolidin, C (O) -t- Substituted with one or two substituents selected from the group consisting of butoxy, phenyl, fluorophenyl, difluorophenyl, cyanophenyl, indolyl, difluoropyrrolidinyl, benzothiazolyl, and N (methyl) C (O) t-butoxy. Has been done.

Suitable 6-14 member spiro rings, fused rings or crosslinked bicyclic rings include 10-azabicyclodecane, 9-azabicyclononane, 8-azabicyclooctane (eg 8-azabicyclo [3.2.1]). ] Octane), azabicycloheptan (eg, 7-azabicycloheptan), 3-azabicyclohexane (eg, 3-azabicyclo [3.1.0] hexane), diazabicyclononane (eg, 1,4-diazabicyclo). [4.3.0] Nonan), diazabicyclooctane, diazabicycloheptan, diazaspirononan, azaspirononan, diazaspiroctane, azaspiroctane, spiro [isobenzofuran-piperidin, diazaspiroheptane, azaspiro Includes, but is not limited to, heptane, octahydrocyclopenta [b] spirol, or octahydrocyclopenta [c] pyrol. In some embodiments, the 6-14 member spiro, fused or crosslinked polycyclic (eg, bicyclic) rings are independently halo, C _1-5 alkyl, C _1-5 haloalkyl, C, respectively. Selected from the group consisting of _1-5 alkoxy, aryloxy, heteroaryloxy, CN, OH, -SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , -CONHR ¹⁰ , C _{3-5 cycloalkyl, aryl and heteroaryl;} And R ¹⁰ are selected from the group consisting of H, C _1-5 alkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl.}

Ｙ^１はＮであり、又は二重結合が存在する場合、Ｙ^１はＣであり；

ｎは０又は１であり；
各Ｒ^６は、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、Ｃ_１−５ハロアルキル、ハロ及びベンジルからなる群から選択され；
ＱはＣＨ、ＣＲ^６又はＮであり；
Ｒ^３及びＲ^４は、それらが結合している窒素原子と一緒になって、３、４、５、６又は７員の単環又は６、７、８、９、１０、１１、１２、１３又は１４員のスピロ環、縮合環及び／又は架橋多環式環を形成する。 In one aspect, the disclosure provides a compound of formula V or V', or a pharmaceutically acceptable salt thereof.

Y ¹ is N, or if a double bond is present, Y ¹ is C;

n is 0 or 1;
Each R ⁶ is selected from the group consisting of _{C 1-5} alkyl, C _3-5 cycloalkyl, C _{1-5 haloalkyl, halo and benzyl;}
Q is CH, CR ⁶ or N;
R ³ and ^{R 4,} together with the nitrogen atom to which they are attached, 3, 4, 5, 6 or 7-membered monocyclic or 6,7,8,9,10,11,12,13 Alternatively, a 14-membered spiro ring, fused ring and / or crosslinked polycyclic ring is formed.

は、ピロール環、シクロペンテン環、チオフェン環、ジヒドロフラン環、ピラゾール環、チアゾール環、又はイミダゾール環である。いくつかの実施形態では、

は、以下からなる群から選択される。

いくつかの実施形態において、

は、

であり、及びＦ、Ｃｌ及びＣ_１−３アルキルからなる群から選択される１〜４個の置換基で任意に置換される。いくつかの実施形態では、

は、

であり、又は

は、

である。いくつかの実施形態では、

は、

であり、又は

は、

である。 In some embodiments

Is a pyrrole ring, a cyclopentene ring, a thiophene ring, a dihydrofuran ring, a pyrazole ring, a thiazole ring, or an imidazole ring. In some embodiments,

Is selected from the group consisting of:

In some embodiments

Is

And are optionally substituted with 1-4 substituents selected from the group consisting of F, Cl and C _{1-3 alkyl.} In some embodiments,

Is

Or

Is

Is. In some embodiments,

Is

Or

Is

Is.

である。いくつかの実施形態では、

からなる群から選択される。いくつかの実施形態では、

である。 In some embodiments,

Is. In some embodiments,

Selected from the group consisting of. In some embodiments,

Is.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered ring. Suitable 3, 4, 5, 6 or 7-membered rings are, but are not limited to, piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, oxazilidinyl, imidazolidinyl, pyrazolydinyl, oxazolidinyl, isoxazolydinyl, thiazolidinyl. , Isothiazolidinyl, azepanyl, diazepanyl or diazabicycloheptane.

であり、
ｍは０、１、２又は３であり；
Ｒ^７及びＲ^９は、それぞれ独立して、ハロ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^８、−ＮＲ^８ＣＯ_２Ｒ^８ａ、−ＳＯ_２Ｒ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＨＲ^８、アリール、及びヘテロアリールからなる群から選択され、又は
２個のＲ^７基はそれらが結合している炭素原子と一緒になって、３、４、５、６、７又は８員のシクロアルキル、３、４、５、６、７又は８員のヘテロシクロアルキル、アリール、又は５もしくは６員のヘテロアリール環を形成し；及び
Ｒ^８及びＲ^８ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、−Ｃ_０−５アルキレン−アリール及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択され；又は
１個のＲ^７基及びＲ^９は、それらが結合している原子と一緒になって５又は６員の複素環又はヘテロアリール環を形成する。 In some embodiments,

And
m is 0, 1, 2 or 3;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _{1-5, respectively.} Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^8, -CONHR ^8, aryl, and heteroaryl, or two ^{R 7} groups taken together with the carbon atoms to which they are attached, 3,4,5,6,7 or 8-membered cycloalkyl, 5, 6, 7 or 8 membered heterocycloalkyl, aryl, or 5 or to form a 6-membered heteroaryl ring; and R ⁸ and ^{R 8a} are each independently , _{H, C 1-5 alkyl, -C 0-5} alkylene - aryl and _{-C 0-5} alkylene - is selected from the group consisting of heteroaryl; or one of ^{R 7} groups and ^{R 9,} and they are attached Together with the atoms, it forms a 5- or 6-membered heteroaryl or heteroaryl ring.

であり；
Ｒ^７及びＲ^９は、それぞれ独立して、ハロ、Ｃ_１−５アルキル、Ｃ_３−５シクロアルキル、ヘテロシクロアルキル、Ｃ_１−５ハロアルキル、Ｃ_１−５ハロアルキレン−ＯＨ、Ｃ_１−５アルキレン−ＣＮ、Ｃ_１−５アルコキシ、Ｃ_１−５ハロアルコキシ、アリールオキシ、ヘテロアリールオキシ、ＣＮ、ＯＨ、−ＮＨＲ^８、−ＮＲ^８ＣＯ_２Ｒ^８ａ、−ＳＯ_２Ｒ^８、−ＣＯ_２Ｒ^８、−ＣＯＮＨＲ^８、アリール、及びヘテロアリールからなる群から選択され、及び
Ｒ^８及びＲ^８ａは、それぞれ独立して、Ｈ、Ｃ_１−５アルキル、−Ｃ_０−５アルキレン−アリール及び−Ｃ_０−５アルキレン−ヘテロアリールからなる群から選択される。 In some embodiments

Is;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _1-5. Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^{Selected from the group consisting of 8} , -CONHR ⁸ , aryl, and heteroaryl, and R ⁸ and R ^8a are independently H, C _1-5 alkyl, -C _0-5 alkylene-aryl and -C, respectively. It is selected from the group consisting of _{0-5 alkylene-heteroaryl.}

In some embodiments, R ⁷ or R ⁹ is _{selected from the group consisting of C 3-5} cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, aryl, and heteroaryl. In some embodiments, R ⁷ groups are oxazolyl or pyridinyl, this respectively, optionally substituted with CN or F. In some embodiments, R ⁷ group is selected from the group consisting of.

In some embodiments, R ⁹ is C _3-5 cycloalkyl. In some embodiments, R ⁹ is cyclopropyl or cyclobutyl, each optionally substituted with 1, 2, 3 or 4 F atoms. In some embodiments, R ⁹ is selected from the group consisting of:

In some embodiments, the compound is selected from the following compounds or pharmaceutically acceptable salts thereof.

In some embodiments, the compounds are further disclosed as the compounds listed in Table 4 (Table D) below, which are used to inhibit SPR.

How to use SPR inhibitors

The use of the compounds and compositions disclosed herein includes their use as SPR inhibitors, analgesics, treatment of acute or chronic pain, anti-inflammatory agents and / or immune cell regulators. The disclosed method comprises inhibiting sepiapterin reductase (SPR) by a method comprising contacting the SPR with a compound or composition disclosed herein in an amount effective to inhibit the SPR. .. In some aspects, the contact method is in vitro. In another aspect, the contact method is in vivo. In various embodiments, the contact method comprises administering the compound or composition to a subject in need thereof. In various embodiments, the subject is a mammal. In a preferred embodiment, the mammalian subject is a human.

SPR inhibitor compounds, compositions, and methods are believed to be useful in the treatment of diseases and disorders associated with the BH4 synthetic pathway, such as, but not limited to, pain, inflammation and immunological disorders. In addition, SPR inhibitor compounds, compositions and methods are found to increase BH4 levels compared to normal subjects who are not known to suffer from pain, inflammation, and / or immune disorders. It is believed to be useful in the treatment of related diseases and disorders, such as, but not limited to, pain, inflammation and immunological disorders. In other embodiments, the subject suffers from pain (eg, acute or chronic pain), inflammation and / or immune impairment.

The disclosed methods include treating a subject suffering from pain such as acute pain or chronic pain, the step of administering to the subject a therapeutically effective amount of a compound or composition disclosed herein. Including. The disclosed method is also a method of treating an inflammation, eg, a subject suffering from chronic inflammation, in which a therapeutically effective amount of a compound or composition disclosed herein is administered to the subject. Including the process. The disclosed methods further include treating a subject suffering from an immunological disorder, comprising administering to the subject a therapeutically effective amount of a compound or composition disclosed herein.

Pain includes AIDS / HIV-related pain, tonic spondylitis, spider inflammation, lower back pain, idiopathic pain, burning oral syndrome, synovitis, cancer pain, carpal canal syndrome pain, horse tail syndrome, central pain syndrome. , Sharco-Marie-Tooth disease, chronic functional abdominal pain, chronic pancreatitis pain, complex local pain syndrome, corneal neuropathic pain, degenerative disc disease, Darkham disease, dermatitis, diabetic peripheral neuropathy, Eras Dunlos syndrome, uterus Endometriosis, apical erythema, lumbar postoperative pain syndrome, fibromyalgia, intercostal nerve pain, interstitial cystitis, irritable bowel syndrome, juvenile dermatitis, lower limb pain, lower limb pain, hemorrhagic syndrome, parenchymal femoral nerve pain , Migraine, multiple sclerosis pain, musculoskeletal pain, myofascial pain, myitis, neuropathic pain, occipital nerve pain, osteoarthritis pain, Paget's disease, pelvic pain, peripheral neuropathy, phantom limb pain, pinched Neurology, rheumatic polymyositis, polymyositis, post-hernia pain syndrome, post-mammectomy pain syndrome, post-stroke pain, post-open chest pain syndrome, post-traumatic neuropathy, post-herpes zoster nerve pain, post-porio syndrome, primary Sexual sclerosis, psoriatic arthritis, pudendal nerve pain, Reynaud's disease, restless lower limb syndrome, rheumatoid arthritis, sacrococcygeal dysfunction, sarcoidosis, sciatic nerve pain,
Postherpetic neuralgia, sickle erythrocyte pain, Schegren's syndrome, spastic oblique neck, Oddi sphincter dysfunction, spinal cord injury, spinal stenosis, syringomyelia, Tarlov cyst, thoracic outlet syndrome (TOS), temporomandibular joint disease, transverse myelitis Includes inflammation, trigeminal neuralgia, ulcerative colitis, vascular pain, syringomyelia, and whipping pain.

Immunological disorders include, but are not limited to, acid-induced lung injury, acne (PAPA), acute respiratory distress syndrome, aging, headache, AIDS, alcoholic hepatitis, alcoholic liver disease, non-alcoholic fatty hepatitis ( NASH), allergen-induced asthma, allergic bronchopulmonary aspergillosis, Alzheimer's disease, muscular atrophic lateral sclerosis (ALS), angina, anhidrosis epiblast dysplasia-ID, tonic spondylitis, antiphosphorus Lipid antibody syndrome, aphthous stomatitis, wormdropitis, arthritis, asthma, atopic dermatitis, autoimmune disease, bee sting-induced inflammation, Bechet's disease, bell paralysis, Blau syndrome, bronchitis, burns, cancer, cardiac hypertrophy, catabolic disorders , Cataract, cerebral aneurysm, cystic fibrosis, chemical stimulation-induced inflammation, chronic heart failure, chronic lung disease in premature infants, chronic obstructive lung disease, colitis, complex local pain syndrome, congenital muscular dystrophy, connective tissue disease , Crohn's disease, cryopyrin-related periodic syndrome, cryptococcus disease, cystic fibrosis, interleukin-1 receptor antagonist deficiency (DIRA), dermatitis, dermatitis, DIPG (pediatric brain stem glioma), endometriosis, Endotoxicemia, eosinophilic esophagitis, familial amyloid polyneuropathy, familial cold urticaria, familial Mediterranean fever, fetal growth, FSHD, glaucoma, glomerular disease, glomerular nephritis, intestinal disease, Peritoneal endometriosis, head trauma, hearing loss, heart disease, Henoch-Schoenlein purpura, hepatitis, hereditary autoinflammatory syndrome, herpes zoster and simplex, HIV-1, Huntington's disease, hyaline membrane disease, hypercholesterolemia , Hyperimmunoglobulin Demia with return fever (HIDS), dysplasia and other anemia, dysplasia, infectious mononuclear spheres, inflammatory bowel disease, inflammatory lung disease, inflammatory neuropathy, inflammatory Equal pain, insect bite-induced inflammation, irritating-induced inflammation, ischemia / reperfusion, Kawasaki disease, kidney disease, kidney damage caused by parasite infection [ml], leptspirosis, leukemia, limb muscular dystrophy 2A, Extremity muscular dystrophy 2B, lung trauma, lupus, lupus nephritis, lymphoma, meningitis, mesopharyngoma, McCull Wells syndrome (urticaria hearing loss amyloidosis), multiple sclerosis, muscle wasting disease, muscular dystrophy, severe myasthenia , Myocarditis, mycobacterial sarcoma, myelodystrophy syndrome, myitis, nasal sinusitis, necrotizing enteritis, neonatal onset multi-organ inflammatory disease (NOMID), nephrosis syndrome, neuritis, neuropathological disease, non-allergen Induced asthma, obesity, eye allergy, organ transplantation, osteoarthritis, middle ear Flame, Paget's disease, pancreatitis, Parkinson's disease, peritonitis, periodic fever, periodontitis, pertussis, pharyngitis and lymphadenitis (PFAPA syndrome), plant stimulant-induced inflammation, pneumocystis infection, turkey / urushi All oil-induced inflammation, nodular polyarteritis, polycystic kidney disease, polymyositis, pontine glioma, psoriasis, psychosocial stress disease, lung disease, pulmonary fibrosis, pulmonary hypertension, necrotizing pyoderma, Purulent aseptic arthritis, renal disease, delayed intellectual development, retinal disease, rheumatic disease, psychodosis, seborrhea, sepsis, sickle erythrocytes, silica-induced disease, Schegren's syndrome, skin disease, sleep apnea, Solid tumors including brain tumors, spinal cord injury, statin-induced myopathy, stroke, submucosal hemorrhage, sunburn, thrombocytopenia, tissue transplantation, TNF receptor-related periodic syndrome (TRAPS), toxoplasmosis, traumatic brain injury , Tuberculosis, type 1 diabetes, type 2 diabetes, ulcerative colitis, vasculitis, and wound repair.

"Therapeutically effective amount" means an amount effective in treating or preventing the onset of a subject being treated or alleviating an existing symptom. The determination of the effective amount is sufficient within the ability of one of ordinary skill in the art, especially in light of the detailed disclosure provided herein. In general, "therapeutically effective dose" refers to the amount of compound that results in achieving the desired effect. For example, in one preferred embodiment, therapeutically effective amounts of the compounds disclosed herein have a reduction in SPR activity of at least 5%, at least 10%, at least 15%, at least 20 as compared to controls. %, At least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, At least 85%, or at least 90%.

The amount of compound administered depends on the subject's age, health, gender and weight, type of co-treatment (if any), severity of distress, nature of desired effect, method and frequency of treatment, and prescription. It can depend on the judgment of the doctor. The frequency of dosing may also depend on the pharmacodynamic effect on arterial oxygen partial pressure. However, the most preferred dose can be tailored to the individual subject as understood and determinable by those skilled in the art without undue experimentation. This typically involves adjusting the standard dose (eg, reducing the dose if the patient is underweight).

Although individual needs vary, determining the optimal range of effective amounts of a compound is within the skill of one of ordinary skill in the art. For administration to humans in the curative or prophylactic treatment of the conditions and disorders identified herein, for example, typical dosages of the compounds of the invention are from about 0.05 mg / kg / day to about. 50 mg / kg / day, eg, at least 0.05 mg / kg, at least 0.08 mg / kg, at least 0.1 mg / kg, at least 0.2 mg / kg, at least 0.3 mg / kg, at least 0.4 mg / kg, Alternatively, it can be at least 0.5 mg / kg, and preferably 50 mg / kg or less, 40 mg / kg or less, 30 mg / kg or less, 20 mg / kg or less, or 10 mg / kg or less, for example about 2.5 mg / kg. The daily dose is from 0.5 mg / kg x 5 kg to about 5000 mg / day (50 mg / kg x 100 kg). For example, the dosage of the compound is from about 0.1 mg / kg / day to about 50 mg / kg / day, from about 0.05 mg / kg / day to about 10 mg / kg / day, from about 0.05 mg / kg / day to about. 5 mg / kg / day, about 0.05 mg / kg / day to about 3 mg / kg / day, about 0.07 mg / kg / day to about 3 mg / kg / day, about 0.09 mg / kg / day to about 3 mg / day kg / day, about 0.05 mg / kg / day to about 0.1 mg / kg / day, about 0.1 mg / kg / day to about 1 mg / kg / day, about 1 mg / kg / day to about 10 mg / kg / day Daily, about 1 mg / kg / day to about 5 mg / kg / day, about 1 mg / kg / day to about 3 mg / kg / day, about 3 mg / kg / day to about 500 mg / day, about 5 mg / day to about 250 mg / day Daily, from about 10 mg / day to about 100 mg / day, from about 3 mg / day to about 10 mg / day, or from about 100 mg / day to about 250 mg / day. Such doses may be administered in a single dose or may be divided into multiple doses.

SPR inhibitors are believed to be useful in the treatment of any condition in which reduced BH4 levels benefit. SPR inhibitors are useful alone or in combination with other compounds that may act to promote the reduction of BH4 levels. This section provides a description of how the SPR inhibitors of the invention can be administered therapeutically to subjects in need thereof.

One of the therapeutic embodiments of the present invention is to provide a subject in need thereof with a composition comprising one or more SPR inhibitors. In one aspect, the SPR inhibitor formulation for treatment in the subject is selected based on the route of administration, and in certain embodiments, liposome and micelle formulations as well as classical pharmaceutical formulations are included.

In various aspects, administration of the composition is systemic or topical and, in yet other embodiments, comprises single site injection of a therapeutically effective amount of the SPR inhibitor composition. Any route known to those of skill in the art for administration of the therapeutic compositions of the present invention, eg, catheters for intravenous, intramuscular, subcutaneous, oral or long-term administration can be considered.

Combination therapy : In addition to therapy based on delivery of the SPR inhibitor composition alone, combination therapy is specifically contemplated. In the context of the present invention, SPR inhibitor composition therapy is considered to be similarly used in combination with other agents commonly used to treat elevated levels of BH4 and / or SPR.

The combination therapy composition is provided in a combined amount effective to produce the desired therapeutic outcome in the treatment of reduced BH4 levels and / or to produce a detectable change in the symptoms described herein. To. This process involves the simultaneous administration of an SPR inhibitor and a second agent or factor. Thus, administering a single composition or pharmacological formulation containing both agents, or two different compositions, one containing the SPR inhibitor therapeutic composition and the other containing the second therapeutic agent. Includes simultaneous administration of the composition or formulation.

Alternatively, treatment with the SPR inhibitor is performed at intervals ranging from minutes to weeks prior to or following treatment with the second therapeutic agent. In embodiments in which the second therapeutic agent and the SPR inhibitor are administered separately, during each delivery time, the second therapeutic agent and the SPR inhibitor can exert an advantageous combined effect. It is generally guaranteed that no significant period will occur. In such cases, manage both modes within about 12-24 hours of each other, or alternately, within about 6-12 hours of each other, or alternately with a delay of only about 12 hours. Can be considered. However, in some situations it is desirable to significantly extend the interval between administrations, in which case between administrations for days (2, 3, 4, 5, 6 or 7) to weeks (2, 3, 4, 5, 6 or 7). 1, 2, 3, 4, 5, 6, 7 or 8 days).

Systemic delivery of SPR inhibitors to patients is a highly efficient method for delivering therapeutically effective amounts of compounds to counteract the immediate clinical manifestations of the disease or disorder. Alternatively, in certain circumstances, topical delivery of SPR inhibitors and / or second therapeutic agents is appropriate. In certain embodiments, it is contemplated that the SPR inhibitor will be delivered to the patient over an extended period of time. In addition, SPR inhibitors are believed to be taken throughout the patient's life to reduce SPR activity levels.

Dosing and pharmaceutical products

Also provided herein are pharmaceutical compositions containing the compounds disclosed herein, along with pharmaceutically acceptable excipients such as diluents or carriers. Compounds and pharmaceutical compositions suitable for use in the present invention include those capable of administering the compound in an amount effective to achieve its intended purpose. The administration of the compounds will be described in more detail below.

Suitable pharmaceutical formulations can be determined by one of ordinary skill in the art, depending on the route of administration and the desired dose. See, for example, Remington's Pharmaceutical Sciences, 1435-712 (18th Edition, Mack Publishing Co, Easton, Pennsylvania, 1990). The pharmaceutical product may affect the physical condition, stability, in vivo release rate and in vivo clearance rate of the administered drug. Depending on the route of administration, the appropriate dose can be calculated according to body weight, body surface area or organ size. Further refinements to the calculations required to determine the appropriate therapeutic dose are excessive, especially taking into account the dose information and assays disclosed herein and the pharmacokinetic data obtained in animal or human clinical trials. It is routinely performed by those skilled in the art without experimenting with.

The phrase "pharmaceutically acceptable" or "pharmacologically acceptable" is a molecular entity that does not cause harmful, allergic, or other adverse reactions when administered to animals or humans. And the composition. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retarders and the like. The use of such excipients for pharmaceutically active substances is well known in the art. Its use in therapeutic compositions is intended unless any conventional vehicle or agent is incompatible with the therapeutic composition. Auxiliary active ingredients can also be incorporated into the composition. In an exemplary embodiment, the formulation is corn syrup solids, high oleic acid Benibana oil, palm oil, soybean oil, L-leucine, tricalcium phosphate, L-tyrosine, L-proline, L-lysine acetate, DATEM. (Emulsion), L-glutamine, L-valine, calcium dibasic phosphate, L-isoleucine, L-arginine, L-alanine, glycine, L-aspartin monohydrate, L-serine, potassium citrate, L-threonine, Sodium citrate, magnesium chloride, L-histidine, L-methionine, ascorbic acid, calcium carbonate, L-glutamic acid, L-cystine dihydrochloride, L-tryptophan, L-aspartic acid, choline chloride, taurine, m-inositol, Ferrous sulfate, ascorbic palmitate, zinc sulfate, L-carnitine, α-tocopherol acetate, sodium chloride, niacinamide, mixed tocopherol, calcium pantothenate, copper sulfate, thiamine chloride hydrochloride, vitamin A palmitate, manganese sulfate, It can include riboflavin, pyridoxin hydrochloride, folic acid, β-carotene, potassium iodide, phylloquinone, biotin, sodium selenate, chromium chloride, sodium molybdate, vitamin D3 and cyanocobalamine.

As used herein, "pharmaceutically acceptable salts" include, for example, base-added salts and acid-added salts.

Pharmaceutically acceptable base addition salts can be formed of metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts of pharmaceutically acceptable compounds can also be prepared using pharmaceutically acceptable cations. Suitable pharmaceutically acceptable cations are well known to those of skill in the art and include alkaline, alkaline earth, ammonium and quaternary ammonium cations. Carbonates or bicarbonates are also possible. Examples of metals used as cations are sodium, potassium, magnesium, ammonium, calcium, ferric and the like. Examples of suitable amines include isopropylamine, trimethylamine, histidine, N, N'-dibenzylethylenediamine, prokine chloride, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and prokine.

Pharmaceutically acceptable acid addition salts include inorganic or organic acid salts. Examples of suitable acid salts include hydrochlorides, formates, acetates, citrates, salicylates, nitrates, phosphates. Other suitable pharmaceutically acceptable salts are well known to those skilled in the art and include, for example, formic acid, acetic acid, sulfonic acid, oxalic acid, tartrate or mandelic acid, hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid; For example, acetic acid, trifluoroacetic acid (TFA), propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, fumaric acid, malic acid, tartaric acid, lactic acid, oxalic acid, gluconic acid, glucanic acid, Organic carboxylic acids such as glucuronic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid, nicotinic acid or isonicotinic acid, sulfonic acid. With acids, sulfos or phosphonic acids or N-substituted sulfamic acids; and with amino acids such as the 20 alpha amino acids involved in the synthesis of natural proteins such as glutamic acid or aspartic acid, and also phenylacetic acid, methanesulfon. Acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane1,2-disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, naphthalene2-sulfonic acid, naphthalene1,5-disulfonic acid, 2- or 3 Included with -phosphoglyceric acid, glucose 6-phosphate, N-cyclohexylsulfamic acid (with cyclamate formation), or other acidic organic compounds such as ascorbic acid.

Pharmaceutical compositions containing the compounds disclosed herein are either conventional methods, such as conventional mixing, dissolution, granulation, dragee manufacturing, trituration, emulsification, encapsulation, encapsulation, or lyophilization processes. Can be prepared with. The appropriate formulation depends on the route of administration chosen.

For oral administration, suitable compositions can be readily formulated by combining the compounds disclosed herein with pharmaceutically acceptable excipients such as carriers well known in the art. .. Such excipients and carriers allow the compound to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, syrups, suspensions and the like for oral ingestion by the patient being treated. To do. Pharmaceutical preparations for oral use are prepared by adding the appropriate adjuncts as needed and then adding the compounds described herein along with solid excipients to obtain tablets or dragee cores. Possibly obtained by grinding the resulting mixture and treating the granular mixture. Suitable excipients include, for example, fillers and cellulose preparations. If desired, a disintegrant can be added. Pharmaceutically acceptable ingredients for a wide variety of formulations are known, such as binders (eg, natural or synthetic polymers), lubricants, surfactants, sweeteners and flavors, coating materials, preservatives. There can be carriers for agents, dyes, thickeners, adjuvants, antibacterial agents, antioxidants and various formulation types.

When a therapeutically effective amount of a compound disclosed herein is administered orally, the composition is typically a solid (eg, tablet, capsule, pill, powder or lozenge) or liquid formulation (eg, aqueous suspension). It is in the form of a turbid liquid, a solution, an elixir agent, or a syrup agent.

When administered in tablet form, the composition can further comprise a functional solid and / or solid support such as gelatin or an adjuvant. Tablets, capsules and powders can contain from about 1 to about 95% compound, and preferably from about 15 to about 90% compound.

When administered in liquid or suspended form, functional liquids and / or liquid carriers such as water, petroleum, or oils of animal or plant origin can be added. The liquid form of the composition may further contain saline, sugar alcohol solution, dextrose or other sugar solution, or glycol. When administered in liquid or suspended form, the composition comprises from about 0.5 to about 90% by weight of the compounds disclosed herein, preferably from about 1 to about 50% by weight of the compounds disclosed herein. May include. In one possible embodiment, the liquid carrier is non-aqueous or substantially non-aqueous. For administration in liquid form, the composition may be supplied as a rapidly dissolving solid preparation for dissolution or suspension immediately prior to administration.

When a therapeutically effective amount of a compound disclosed herein is administered by intravenous, dermal or subcutaneous injection, the composition is in the form of a pyrogen-free, parenterally acceptable aqueous solution. Preparation of such parenterally acceptable solutions in consideration of pH, isotonicity, stability and the like is within the skill of one of ordinary skill in the art. Preferred compositions for intravenous, dermal or subcutaneous injection typically include isotonic vehicles in addition to the compounds disclosed herein. Such compositions can be prepared for administration as a solution of a free base or pharmacologically acceptable salt appropriately mixed in water with a surfactant such as hydroxypropyl cellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof, and in oils. Under normal storage and use conditions, these preparations can optionally contain preservatives to prevent the growth of microorganisms.

Injectable compositions may include sterile aqueous solutions, suspensions, or dispersions, and sterile powders for the immediate preparation of sterile injectable solutions, suspensions, or dispersions. In all cases, the form must be sterile and fluid enough to be easily injected. It must be stable under manufacturing and storage conditions and must resist the contaminating effects of microorganisms such as bacteria and fungi by optionally including preservatives. The carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyols (eg, glycerol, propylene glycol, liquid polyethylene glycol, etc.), suitable mixtures thereof, and vegetable oils. In one possible embodiment, the carrier is non-aqueous or substantially non-aqueous. Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, in the case of dispersions by the maintenance of the required particle size of the compound, and by the use of surfactants. Prevention of microbial action can be provided by various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases it will be preferable to include isotonic agents such as sugar or sodium chloride. Sustained absorption of the injectable composition can be achieved by using agents that delay absorption, such as aluminum monostearate and gelatin, in the composition.

Sterilized injectable solutions are prepared by adding the required amount of the active compound in a suitable solvent with the various other ingredients listed above as needed and sterilizing by filtration. Generally, dispersions are prepared by incorporating various sterile active ingredients into a sterile vehicle containing a basic dispersion medium and other required ingredients from those listed above. For sterile powders for the preparation of sterile injectable solutions, preferred preparation methods are vacuum drying and lyophilization techniques that yield powders of any additional desired ingredients in addition to the active ingredient from the pre-sterilized filtered solution.

Sustained-release or sustained-release formulations can also be prepared to achieve controlled release of active compounds in contact with body fluids in the gastrointestinal tract and to provide substantially constant and effective levels of active compounds in plasma. For example, release can be controlled by one or more of dissolution, diffusion, and ion exchange. In addition, sustained release approaches can enhance absorption through saturated or limited pathways in the gastrointestinal tract. For example, the compound may be embedded in a polymer matrix of biodegradable polymers, water soluble polymers or a mixture of both, and optionally suitable surfactants for this purpose. Embedding can mean, in this context, embedding fine particles in a matrix of polymers. Emission-controlled formulations are also obtained by encapsulation of dispersed microparticles or emulsified microdroplets via known dispersion or emulsion coating techniques.

For administration by inhalation, the compounds of the invention are conveniently delivered in the form of aerosol spray presentation from a pressure pack or nebulizer, with the use of suitable propellants. For pressurized aerosols, the dose unit can be determined by providing a valve for delivering the measured amount. Capsules and cartridges such as gelatin for use in inhalers or inhalers can be formulated to contain a powder mixture of the compound and a suitable powder base such as lactose or starch.

The compounds disclosed herein can be formulated for parenteral administration by injection (eg, by bolus injection or continuous infusion). The injectable product can be provided in a unit dosage form (eg, ampoule or multi-dose container) with preservatives added. The composition may take the form of a suspension, solution or emulsion in an oily or aqueous vehicle and may contain a formulation such as a suspending agent, stabilizer and / or dispersant.

Pharmaceutical formulations for parenteral administration include aqueous solutions of compounds in water-soluble form. In addition, suspensions of compounds can be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils or synthetic fatty acid esters. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound and allow the preparation of high concentration solutions. Alternatively, the composition may be in powder form for composition with a suitable vehicle (eg, sterile water containing no pyrogens) prior to use.

The compounds disclosed herein can also be formulated in rectal compositions such as suppositories or retention enemas (eg, containing conventional suppository bases). In addition to the formulations described above, the compounds can also be formulated as depot formulations. Such long-acting preparations can be administered by transplantation (eg, subcutaneous or intramuscular) or intramuscular injection. Thus, for example, the compound can be formulated as a suitable polymer or hydrophobic material (eg, as an emulsion in an acceptable oil) or ion exchange resin, or as a sparingly soluble derivative, eg, as a sparingly soluble salt.

In particular, the compounds disclosed herein are in the form of tablets containing excipients such as starch or lactose, or in the form of capsules or granules, alone or in admixture with excipients, or elixir. It can be administered orally, orally or sublingually in the form of a suspension containing an agent or flavoring agent or coloring agent. Such liquid preparations can be prepared with pharmaceutically acceptable additives such as suspending agents. The compounds can also be injected parenterally, eg, intravenously, intramuscularly, subcutaneously, or intracoronary. For parenteral administration, the compound is most often used in the form of sterile aqueous solutions that can contain other substances, such as salts, or sugar alcohols such as mannitol or glucose, to make a solution isotonic with blood. To.

For veterinary use, the compounds disclosed herein are administered as an appropriately acceptable formulation according to conventional veterinary practice. The veterinarian can easily determine the most appropriate dosing regimen and route of administration for a particular animal.

In some cases, all components required for the treatment of SPR-related disorders using the compounds disclosed herein alone or in combination with interventions or other agents traditionally used in the treatment of SPR-related disorders. Can be packaged in a kit. Specifically, the invention is a set of packaged agents comprising the compounds disclosed herein, as well as buffers and other ingredients for preparing deliverable forms of said agents, and / or. A device for delivery of said agent and / or any agent used in combination therapy with the compounds disclosed herein, and / or instructions for the treatment of a disease packaged with the agent. Provided are kits used for therapeutic intervention of diseases including. Instructions may be on printed paper, computer-readable magnetic or optical media, or any tangible medium such as instructions for referencing remote computer data sources such as worldwide web pages accessible over the Internet. It may be fixed.

Synthesis of compounds disclosed herein

The compounds disclosed herein can be prepared according to the methods detailed in the Examples, with appropriate modifications to the starting reagents. Taking into account the teachings of the examples, one of ordinary skill in the art can synthesize the compounds disclosed herein using typical organic chemistry techniques.

In some cases, the appropriate thiouracil is converted to a hydrazine intermediate and the hydrazine intermediate is coupled with the appropriate enamine reagent to form a compound of formula I or an intermediate with a pyrazolyl moiety, and an intermediate with a pyrazolyl moiety. Preparing compounds of formula I as shown in Scheme 1 and Scheme 2 by reacting the body to couple with the appropriate amine (eg, using reagents such as HATU or HATU / HOAt). Can be done.

Scheme 1

Scheme 2

In some cases, the compound of formula I converts the appropriate dichloropyrimidine to a hydrazine intermediate and couples the hydrazine intermediate with a suitable enamine reagent to form an intermediate with a pyrazolyl moiety, which further provides the pyrazolyl moiety. The intermediate having can be prepared by coupling with a suitable amine (eg, using a reagent such as HATU or HATU / HOAt) to obtain a compound of formula I as shown in Schemes 3 and 4. it can.

Scheme 3

Scheme 4

In some cases, the compound of formula I converts the appropriate cyclopentanone to a hydrazine intermediate and couples the hydrazine intermediate with a suitable enamine reagent to form an intermediate with a pyrazolyl moiety, which further comprises the pyrazolyl moiety. Can be prepared by coupling an intermediate with (eg, using a reagent such as HATU or HATU / HOAt) with a suitable amine to give a compound of formula I as shown in Scheme 5. ..

In some cases, the compound of formula I couples the appropriate hydrazine intermediate with the appropriate enamine, enol ether, aldehyde or ketone reagent to form an intermediate with a pyrazolyl moiety, further with a pyrazolyl moiety. The body can be prepared by coupling with a suitable amine (eg, using a reagent such as HATU or HATU / HOAt) to obtain a compound of formula I as shown in Scheme 6.

Scheme 6

In some cases, the compound of formula I couples the appropriate hydrazine intermediate with the appropriate dialdehyde reagent to form an intermediate with a pyrazolyl moiety, and further reacts the intermediate with the pyrazolyl moiety to be suitable. It can be prepared by coupling with an amine (eg, using a reagent such as HATU or HATU / HOAt) to obtain a compound of formula I as shown in Scheme 7.

Scheme 7

In some cases, the compound of formula I couples the appropriate pyrazolyl moiety with the appropriate chloropyrimidine or sulfonylpyrimidine to form an intermediate with the compound or pyrazolyl moiety of formula I, further with the pyrazolyl moiety. The body is reacted to couple with the appropriate amine (eg, using reagents such as HATU or HATU / HOAt) to obtain compounds of formula I as shown in Schemes 8, 9, 10 and 11. Can be prepared by.

Scheme 8

Scheme 9

Scheme 10

Scheme 11

In some cases, the appropriate pyrazolyl moiety and the appropriate bromo-cyclopropyridene acetate are coupled to form an intermediate with the pyrazolyl moiety, which is further reacted with the intermediate having the pyrazolyl moiety (eg, HATU or HATU /). A compound of formula I can be prepared by coupling with a suitable amine (using a reagent such as HOAt) to obtain a compound of formula I as shown in Scheme 12.

Scheme 12

In some cases, the compound of formula I couples the appropriate azide with the appropriate β-ketoester to form an intermediate with a triazolyl moiety and then reacts the intermediate with a triazolyl moiety (eg HATU or It can be prepared by coupling with a suitable amine (using a reagent such as HATU / HOAt) to obtain a compound of formula I as shown in Scheme 13.

Scheme 13

Non-commercially available amines can be prepared using standard procedures. In some cases, non-commercially available amines couple suitable aryl bromide with a protected cyclic diamine, followed by deprotection of the amine protecting group, for example amines as shown in Scheme 14. It can be prepared by obtaining.

Scheme 14

In some cases, the appropriately protected aminoketone is reduced to obtain the corresponding alcohol, the alcohol is protected with the appropriate protecting group, and the appropriate reagent is added to the protected alcohol with the desired functional group (eg, cyano group). ), And then the amine protecting group is deprotected to obtain an amine as shown in scheme 15, for example, a non-commercially available amine can be prepared.

Scheme 15

Evaluation of SPR inhibitory activity

The compounds disclosed herein can be evaluated for SPR inhibitory activity. Typically, the compounds are enzyme assays (eg, TR-FRET assays) and / or cell assays (eg, SKN-N-BE (2) cells or human PBMCs (peripheral blood mononuclears), as described below. Evaluated by cells)).

TR-FRET Assay: The TR-FRET (uniform, time-resolved, fluorescence resonance energy transfer) assay was used to evaluate the activity of the compounds under standard assay conditions. Terbium-labeled SNAP-hSPR and SSZ (sulfasalazine) -labeled SNAP-EGFP were used as protein pairs in this assay according to the procedure described in Haruki et al., Science, 430: 987 (2013). Compounds were screened at different concentrations and IC50 values were calculated.

SKN-N-BE (2) Cell Assay: SK-N-BE (2) cells were seeded on sterile 96-well plates and incubated at 37 ° C. for 12-24 hours with _{a 5% CO 2 supply.} Medium was removed and fresh DMEM / F-12 medium (containing glutamine and Pen / Strep but not FBS) was added. Compounds (at different concentrations) were added to different wells. The plates were then _{incubated with a 5% CO 2} supply at 37 ° C. for 6-48 hours. The plate was then centrifuged and the supernatant was removed. The plate was then optionally washed once with PBS. They were then sealed and stored at -80 ° C or used immediately. Cells were lysed and BH4 levels were evaluated by LC-MS.

hPBMC Assay: PBMCs were purchased or isolated from fresh human blood and used as fresh preparations or frozen for later use. The assay system was prepared by pretreating the assay plate overnight with a solution containing anti-human CD3 antibody. Human PBMC were suspended in assay medium and seeded in assay plates at a density of 1 to 4 × 10 ⁵ cells per well. The desired concentration of test compound was added to each well. A solution of human anti-CD28 antibody was also added to each well. The plates were incubated at 37 ° C. and 5% CO ₂ for 12-48 hours. The assay plate was centrifuged at 1-3000 RMP for 5-15 minutes and the supernatant was removed. Cells were lysed, sealed and used directly or frozen at -80 ° C. The amount of inhibition of BH4 production was quantified using LC-MS.

Evaluation of pain behavior

The compounds disclosed herein can be evaluated for their effect on pain behavior. Typically, the compound is evaluated by a behavioral pharmacology model as follows.

Behavioral pharmacological model: Two neuropathy Surgery: Forced oral administration of compounds to rats undergoing one of a chronic sciatic nerve stenosis injury or a preliminary neuropathy that damages two of the three peripheral branches of the sciatic nerve did. As a measure of neuropathic pain-like behavior, the foot withdrawal response threshold to mechanical stimuli with calibrated von Flyfilament was used.

The following abbreviations are used throughout the examples and specifications.

General procedure

The following LC-MS analysis method was used.

The following preparative HPLC and SFC methods were used.

The following preparative chiral separation and analysis methods were used.

The following LC-MS method was used.

Preparation Example 1-Method 1: Formation of intermediates from the corresponding thiouracil

Preparation of Intermediate 1: 2-hydrazinyl-6-methyl-3,4-dihydropyrimidine-4-one

Step 1: Synthesis of 6-methyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one

NaOH (97%, 15.7 g, 381 mmol) was added to water (500 mL) and the suspension was stirred at room temperature for 10 minutes. 6-Methyl-2-sulfanilidene-1,2,3,4-tetrahydropyrimidine-4-one (98%, 53.5 g, 369 mmol) was added and the mixture was stirred for 10 minutes until completely dissolved. Iodomethane (28.99 mL, 461 mmol) was added dropwise and the mixture was stirred at room temperature for 4 hours. The colorless solid was filtered, washed with ice-cold water (2 x 100 mL) and dried under vacuum at 60 ° C. to give the title compound (57 g, 98%) as a colorless solid.

Method A: LC-MS m / z = 156.9 [M + H] ⁺ ; RT = 0.61 minutes.

Step 2: Synthesis of 2-hydrazinyl-6-methyl-3,4-dihydropyrimidine-4-one (Intermediate 1)

Hydrazine hydrate (15.75 mL, 0.32 mol) in a stirred solution of 6-methyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one (11.9 g, 76.18 mmol) in EtOH (30 mL). ) Was added, and the mixture was stirred at 80 ° C. for 5.5 hours. The reaction mixture was cooled to room temperature, the resulting precipitate was collected, dried by vacuum filtration and washed with water (3 mL) to give the title compound (9.20 g, 85%) as an off-white powder.

Method A: LC-MS m / z = 140.90 [M + H] ⁺ ; RT = 0.18 minutes.

Intermediate 2: Preparation of 5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylic acid

Step 1: Synthesis of methyl-5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylate

Methyl (2Z) -2-[(dimethyl) in an EtOH (70 mL) stirred suspension of hydrazinyl-6-methyl-3,4-dihydropyrimidine-4-one (intermediate 1,6.82 g, 48.66 mmol). Amino) methylidene] -3-oxobutanoate (8.33 g, 48.66 mmol) (intermediate 3) was added, followed by AcOH (9.75 mL), and the mixture was stirred at 80 ° C. for 1 hour. The reaction mixture is cooled to room temperature, at which point the product precipitates from the solution, filtered under vacuum, washed slightly with EtOH, as the title compound (6.02 g, 50%) as a fluffy pale pink powder. Got

Method A: LC-MS m / z = 248.95 [M + H] ⁺ ; RT = 1.01 minutes.

Step 2: Synthesis of 5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylic acid (intermediate 2)

THF (40 mL) of methyl-5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylate (6.02 g, 24.25 mmol) ) A 3M aqueous NaOH solution (40.42 mL) followed by water (20 mL) was added to the stirred suspension to assist dissolution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to remove THF and acidified to pH 6 with 1M aqueous HCl. The resulting white solid was filtered under vacuum, washed with Et 2 _O, and dried to afford as an off-white powder title compound (5.45g, 96%).

Method A: LC-MS m / z = 234.9 [M + H] ⁺ ; RT = 0.84 minutes.

Preparation of Methyl Intermediate 3: 2-[(Dimethylamino) Methylidene] -3-oxobutanoate

Methyl 3-oxobutanoate (40 g, 0.34 mol) and 1,1-dimethoxy-N, N-dimethylmethaneamine (54.92 mL, 0.41 mol) were combined and stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under vacuum and the resulting oil was dried under vacuum for 24 hours to give 56.53 g (86.3%) of the title compound as a dark red solid: ¹ H NMR (500 MHz, DMSO-d6) δ7.62 (s, 1H), 3.63 (s, 3H), 3.24-2.96 (m, 3H), 2.90-2.58 (m, 3H), 2. 13 (s, 3H).

Preparation of Intermediate 4: 2-Ethyl-2,3-dihydro-1H-indole

Intermediates were formed using the procedure described in US Patent Publication No. 2011/0021500.

At room temperature, a solution of 2-ethyl-1H-indole (1 g, 6.89 mmol) in acetic acid (15 ml) was treated little by little with sodium cyanoborohydride (2.03 g, 32.37 mmol). The addition caused foaming and slight exotherm. The resulting suspension was stirred at room temperature for 20 hours. The reaction mixture was concentrated under vacuum and the residue was washed with 4M aqueous HCl (30 mL). The mixture was stirred at room temperature for 1 hour, then cooled to 0 ° C. and treated with 4M aqueous NaOH solution (40 mL). When the addition was complete, the mixture was extracted with EtOAc (x2). The extract was washed with brine _{, dried on sulfonyl 4} and concentrated under vacuum to give the title compound (1.1 g, 97%) as a pale yellow mobile oil.

Method A: LC-MS m / z = 147.9 [M + H] ⁺ ; RT = 0.96 minutes.

Example 1-6-Methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine- 4-on synthesis

DMF of 5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazol-4-carboxylic acid (intermediate 2, 6.60 g, 28.18 mmol) To the (80 mL) stirred solution, add COMU (13.28 g, 31.00 mmol), DIPEA (12.06 mL, 70.45 mmol) and 1,2,3,4-tetrahydroisoquinoline (3.93 mL, 31.00 mmol). , Stirred at room temperature for 1 hour. The reaction mixture _{was quenched by the addition of saturated NaHCO 3} solution (20 mL) and water (20 mL) and extracted with DCM (4 x 100 mL). The combined organic extracts were dried over sodium sulphate, concentrated under vacuum and milled with MeCN to give the title compound (4.71 g, 48%) as an off-white powder.

Method C: LC-MS m / z = 350.1 [M + H] ⁺ ; RT = 2.54 minutes.

Example 2-39-Synthesis of dihydropyrimidinone

Examples 2-39 follow the procedure described in Example 1 for intermediate 2 (5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole). -4-carboxylic acid) was prepared by reacting with the appropriate amine and the coupling agent specified in Table 10 (Table 1). All amines used in Table 10 (Table 1) were commercially available, with the exception of Example 38, which was synthesized with Intermediate 4 (2-ethyl-2,3-dihydro-1H-indole).

Example 40-43-Chiral separation

Examples 40-43 of Table 11 (Table 2) were prepared by chiral separation of the racemic compounds of Table 10 (Table 1). Stereochemistry was arbitrarily assigned.

Examples 44-5-chloro-6-methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4 − Dihydropyrimidine-4-one

6-Methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazol-1-yl] -3,4-dihydropyrimidine-4-one ( Example 1, Q-279 (EV-AO7529-002), 100 mg, 0.286 mmol) was added to an AcOH (2 mL) solution, NCS (40 mg, 0.301 mmol) was added, and the mixture was stirred at 90 ° C. for 1 hour. The reaction mixture was concentrated under vacuum and milled with MeCN to give the title compound (60 mg, 54%) as a white powder.

Method C: LC-MS m / z = 384.2 [M + H] ⁺ ; RT = 2.99 minutes.

Example 45-5-5-chloro-6-methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4 -Synthesis of dihydropyrimidine-4-one

6-Methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazol-1-yl]-using the procedure described in Example 44. Chlorination of 3,4-dihydropyrimidine-4-one (Example 7, Q-359 (EV-AP2325-001)) gave the title compound (54 mg, 42%) as a white powder.

Method C: LC-MS m / z = 404.2 [M + H] ⁺ ; RT = 2.88 minutes.

Example 46-6-Methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-ylmethyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine- 4-on synthesis

6-Methyl-2- [5-methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazol-1-yl] -3,4-dihydropyrimidine-4-one ( _{Example 1, LiAlH 4} (216 μL, 0.519 mmol) was added to a stirring solution of Q-279 (EV-AO7529-002), 165 mg, 0.472 mmol in THF (3 mL) at 0 ° C., and the mixture was stirred at room temperature for 1 hour. did. The reaction mixture was quenched by the addition of water (4 mL), NaOH (4 mL), and then water (4 mL). The reaction mixture was acidified to pH 5 with acetic acid and then neutralized to pH 7 with saturated sodium bicarbonate solution. The reaction mixture was extracted with DCM (3 x 40 mL), the combined organic extract _{was dried over Na 2} SO ₄ , concentrated under vacuum and ground with MeCN (3 mL) to give the title compound (57 mg, 35). %) Was obtained as a white powder.

Method C: LC-MS m / z = 336.1 [M + H] ⁺ ; RT = 1.29 minutes.

Preparation Example 2-Preparation of intermediate thiouracil and thioether

Preparation of Intermediate 5: 2-Sulfanilidene-1H, 2H, 3H, 4H-Pyrazolo [1,5-a] [1,3,5] Triazine-4-one

Step 1: Synthesis of ethyl N-[(1H-pyrazole-5-yl) carbamoti oil] carbamate

Ethyl N-carbotioil carbamate (3.96 ml, 0.03 mol) for 5 minutes (slight exotherm) was added to a solution of 1H-pyrazole-5-amine (3 g, 36.1 mmol) in acetone (50 ml). The mixture was stirred at room temperature for 2 hours. The yellow solution was treated with ice-cold water (50 ml), which caused a transient precipitate. The flask was cooled in ice to form a precipitate. The solid was collected by filtration, washed with water and dried under vacuum to give the title compound (5.0 g, 46%) as a yellow solid.

Method A: LC-MS m / z = 214.90 [M + H] ⁺ ; RT = 0.94.

Step 2: Synthesis of 2-sulfanilidene-1H, 2H, 3H, 4H-pyrazolo [1,5-a] [1,3,5] triazine-4-one

To ethyl N-[(1H-pyrazole-5-yl) carbamochi oil] carbamate (2.5 g, 11.67 mmol) was added an aqueous 2M NaOH solution (23.3 ml), and the mixture was stirred at room temperature for 2 hours. The solution was acidified with concentrated H ₂ SO ₄ and the resulting precipitate was filtered under vacuum to give a pale yellow powder. Purification by recrystallization with water gave the title compound (1.54 g, 94%) as a pale yellow powder.

Method A: LC-MS m / z = 168.95 [M + H] ⁺ ; RT = 0.19.

Preparation of Intermediate 6: 2-Sulfanilidene-1,2,3,4,5,6,7,8-octahydroquinazoline-4-one

Thiourea (5.37 g, 70.5 mmol) and DBU (13.15 ml, 88.13 mmol) in a MeCN (40 ml) solution of ethyl 2-oxocyclohexane-1-carboxylate (9.40 ml, 58.75 mmol). In addition, it was stirred at 80 ° C. overnight.

The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The reaction mixture was acidified to pH 3/4 with 5M aqueous HCl, the precipitate was filtered _{, washed with H 2} O and Et ₂ O and dried under vacuum to give the title compound (10.70 g, 98%). Obtained as an off-white powder.

Method A: LC-MS: m / z = 183.0 (M + H) ⁺ ; RT = 0.71.

Synthesis of Intermediate 7: 6-Methyl-4-sulfanilidene-1,2,3,4-tetrahydropyrimidine-2-one

2,4-Bis (4-methoxyphenyl) -1 in a solution of 6-methyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (2.0 g, 15.86 mmol) in dioxane (30 ml). , 3,2,4-Dithiadiphosphethane 2,4-disulfide (6.41 g, 15.86 mmol) was added, and the mixture was stirred at 100 ° C. for 2 hours. The reaction mixture was cooled to room temperature and the white precipitate was filtered under vacuum and washed with dioxane (20 ml) to give the title compound (1.85 g, 82%) as an off-white powder.

Method B: LC-MS: m / z = 142.85 (M + H) ⁺ ; RT = 0.36.

Synthesis of intermediate 8: 3,6-dimethyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one

3,6-Dimethyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one from (3E) -1,1,1-trichloro-4-methoxypenta-3-en-2-one , Zanatta, Nilo; Madruga, Claudia C.I. Marisco, Patricia C.I. Da Rosa, Luciana S.A. Da Silver, Fabio M. et al. Bonacorso, Helio G. et al. Martins, Marcos A. P. Journal of Heterocyclic Chemistry; vol. 47; nb. 5; (2010); p. The title compound (4.68 g, 78%) was obtained as a brown powder according to the procedure described in 1234-1239.

Method A: LC-MS: m / z = 170.95 (M + H) ⁺ ; RT = 0.97 minutes.

Examples 47-54

Table 12 in the same manner as in Example 1, starting with the corresponding commercially available thiouracil, methylthioether or a particular intermediate, coupling the intermediate acid with the appropriate amine using the particular coupling conditions. Examples 47-54 of (Table 3) were prepared.

Example 55-56-Chiral Separation

Examples 55-56 of Table 13 (Table 4) were prepared by chiral separation of the racemic compounds of Table 12 (Table 3). Stereochemistry was arbitrarily assigned.

Preparation Example 3-Formation of Intermediates from Corresponding Dichloropyrimidines

Preparation of Intermediate 9: 2-Chloro-3H, 4H-Tieno [3,2-d] Pyrimidine-4-one

A 5 M aqueous NaOH solution (98 mL, 488 mmol) was added to a stirred solution of 2,4-dichlorothieno [3,2-d] pyrimidine (20 g, 97.5 mmol) in THF (80 mL), and the mixture was stirred at 50 ° C. for 6 hours. The reaction mixture was acidified to pH 5 with acetic acid. The solution was then extracted with EtOAc (2 x 50 mL) and the combined organics were _{dried over Na 2} SO ₄ , filtered and concentrated in vacuo with the title compound (11.3 g, 60.5 mmol, 62%). ) Was obtained as a yellow powder.

Method A: LC-MS m / z = 186.9 [M + H] ⁺ ; RT = 0.77 minutes.

Preparation of Intermediate 10: 2-Hydrazinyl-3H, 4H-Tieno [3,2-d] Pyrimidine-4-one

Hydrazine hydrate (5.91 mL, 121.) In a stirred solution of 2-chloro-3H, 4H-thieno [3,2-d] pyrimidin-4-one (11.34 g, 60.8 mmol) in EtOH (90 mL). 5 mmol) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled to room temperature. The resulting precipitate was collected by filtration and washed with water (15 mL) to give the title compound (7.4 g, 40.6 mmol, 67%) as a pale yellow powder.

Method A: LC-MS m / z = 182.9 [M + H] ⁺ ; RT = 0.18 minutes.

Intermediate 11: 5-Methyl-1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid

Step 1: Synthesis of methyl-5-methyl-1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate

In a stirred solution of 2-hydrazinyl-3H, 4H-thieno [3,2-d] pyrimidin-4-one (7 g, 38.4 mmol) with EtOH (75 mL) and AcOH (7.70 mL, 134.5 mmol). (2Z) -2-[(dimethylamino) methylidene] -3-oxobutanoate (7.89 g, 46.1 mmol) was added, and the mixture was stirred at 50 ° C. for 3 hours. The reaction mixture was cooled to room temperature and the resulting precipitate was isolated by filtration to give the title compound (11.2 g, 22.5 mmol, 59%) as a pale yellow powder.

Method A: LC-MS m / z = 291.0 [M + H] ⁺ ; RT = 1.15 minutes.

Step 2: Synthesis of 5-methyl-1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid

Methyl-5-methyl-1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate (6.53 g, 22.5 mmol) A 2.5 M aqueous NaOH solution (54 mL, 135 mmol) was added to a 2: 1 solution of THF / methanol (37 mL), and the mixture was stirred at room temperature for 2 hours. The organic matter was removed under vacuum and the residue was acidified to pH 5 with a 2M HCl aqueous solution and the resulting precipitate was collected by filtration to give the title compound (6.22 g, 19.9 mmol, 89%) as a beige powder. It was.

Method A: LC-MS m / z = 277.0 [M + H] ⁺ ; RT = 0.97 minutes.

Preparation of Intermediate 12: 2-Methyl-4- (trifluoromethyl) piperidine (4: 1 mixture of diastereoisomers)

A solution of 2-methyl-4- (trifluoromethyl) pyridine (800 mg, 4.97 mmol) in 25% acetic acid in MeOH (100 ml) [0.05 M], H-cube [10% Pt-supported C cartridge, 90 bar and The reaction was carried out at 80 ° C. and 1 ml / min. Upon completion, the reaction mixture was treated with a dioxane solution of 4M HCl (2 ml, 8 mmol) and then concentrated in vacuo to give a white solid. The solid was dissolved in MeOH, treated with ammonia (7M in MeOH) and concentrated under reduced pressure to give the title compound (270 mg, 32%) as a white solid.

Method A: LC-MS m / z = 168.00 [M + H] ⁺ ; RT = 0.17 minutes.

Preparation of Intermediate 13: 4- (1-Cyano-1-Methylethyl) Piperidine-1-ium Chloride

Step 1 : Synthesis of tert-butyl 4- (1-cyano-1-methylethyl) piperidine-1-carboxylate

KHMDS (1M in toluene, 2.68 mL, 2.68 mmol) in a stirred solution of tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate (0.2 g, 8.13 mmol) in dry THF (2 mL) at 0 ° C. Was added slowly. The reaction mixture was stirred for 10 minutes, after which a solution of iodomethane (0.11 mL, 1.78 mmol) in dry THF (2 mL) was added slowly. The reaction was warmed to room temperature and stirred overnight. The reaction mixture was quenched with aqueous ammonium chloride solution and extracted with ethyl acetate. The extract was dried (Na ₂ SO ₄ ) and concentrated in vacuo to give the title compound (246 mg, 98%) as a yellow powder: ^{1 1} H NMR (250 MHz, chloroform-d) δ4.20 (s,, 2H), 2.63 (m, 2H), 1.80 (m, 2H), 1.47 (s, 3H), 1.46 (s, 9H), 1.33 (s, 6H).

Step 2: Synthesis of 4- (1-cyano-1-methylethyl) piperidine-1-ium chloride

Suspend tert-butyl 4- (1-cyano-1-methylethyl) piperidine-1-carboxylate (EV-AQ8828-001,243 mg, 0.963 mmol) in HCl (4 M in dioxane, 7 mL) to disperse the reaction. The mixture was stirred at room temperature for 3 hours. The resulting precipitate was filtered and washed with ether to give the title compound (95 mg, 51%) as a yellow powder: ¹ H NMR (500 MHz, DMSO-d6) δ8.96 (s, 1H), 8 .51 (s, 1H), 2.87-2.78 (m, 2H), 1.95-1.87 (m, 2H), 1.72-1.63 (m, 1H), 1.54 -1.45 (m, 2H), 1.29 (s, 6H).

Example 57-74-Synthesis of thienopyrimidine

Examples 57-74 of Table 14 (Table 5) show Intermediate 11 (5-methyl-1- {4-oxo-3H, 4H-thieno [3,2-d], using the method described in Example 1. ] Pyrimidine-2-yl} -1H-pyrazole-4-carboxylic acid) was prepared by reacting with a suitable amine using a specific coupling reagent.

Examples 75-2-{4-[(2R, 6S) -2,6-dimethylpiperidine-1-carbonyl] -5-methyl-1H-pyrazole-1-yl} -3H, 4H-thieno [3,2 −D] Preparation of pyrimidine-4-one

5-Methyl-1- {4-oxo-3H, 4H-thiono [3,2-d] pyrimidin-2-yl} -1H-pyrazol-4-carboxylic acid (intermediate 11, (EV-AP2386-001)) Thionyl chloride (0.2 ml, 2.71 mmol) and then DMF (cat, 1 drop) were added to a solution of (75 mg, 0.27 mmol) in DCM (5 ml), and the mixture was stirred at 50 ° C. for 2 hours. The reaction mixture was concentrated under vacuum, DCM was added and the concentration was repeated (x2). The crude acid chloride (assumed to be 0.271 mmol) was further suspended in DCM (5 ml) at 0 ° C. to (cis) -2,6-dimethylpiperidine (0.04 ml, 0.41 mmol) and triethylamine (0.09 ml). , 0.68 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with water (5 mL) and brine solution (5 mL) and the organic fraction was concentrated under vacuum. The crude residue was dissolved in THF: 1M NaOH (1: 1, 2 mL) and stirred at room temperature. Methanol (0.5 ml) was added. The organic matter was evacuated from the reaction mixture and the reaction mixture was acidified to pH 5 with 1M aqueous HCl. The aqueous layer was extracted with DCM (2 x 5 mL) and the combined organic extracts were _{dried over Na 2} SO ₄ , filtered and concentrated under vacuum. The crude residue was purified by preparative HPLC (Method G) to give the title compound (14.2 mg, 14%) as an off-white powder.

Method A: LC-MS m / z = 372.2 [M + H] ⁺ ; RT = 3.05 minutes.

Examples 76-77

The examples in Table 15 (Table 6) were prepared by chiral separation of the racemic compounds in Table 14 (Table 5). Stereochemistry was arbitrarily assigned.

Preparation Example 4 Formation of Intermediates from Corresponding Dichloropyrimidines

Preparation of Intermediate 14: 2-Chloro-4-methoxy-6-methylpyrimidine

To a solution of 2,4-dichloro-6-methylpyrimidine (1 g, 6.14 mmol) in THF (10 ml) was added MeOH (18.4 ml, 9.20 mmol) in which 0.5 M NaOMe was dissolved at 0 ° C. to room temperature. Stirred overnight. Further, 0.5 equivalents of MeOH in which 0.5 M NaOMe (6.14 ml, 3.07 mmol) was dissolved was added at 0 ° C., and the reaction was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine (20 ml), dried, concentrated under reduced pressure and the residue was purified by column chromatography (100: 0-75: 25 heptane- EtOAc) with the title compound (275 mg, 28%) was obtained as a colorless crystalline solid.

Method A: LC-MS m / z = 158.9 [M + H] ⁺ ; RT = 1.05 minutes.

Preparation of Intermediate 15: 5-Chloro-6H, 7H- [1,3] thiazolo [5,4-d] pyrimidin-7-one (EV-AQ0263-001)

Step 1: Synthesis of 7- (benzyloxy) -5-chloro- [1,3] thiazolo [5,4-d] pyrimidine

Benzyl alcohol (495 μl, 4.76 mmol) and hydride at 0 ° C. in a solution of 5,7-dichloro- [1,3] thiazolo [5,4-d] pyrimidine (980 mg, 4.76 mmol) in THF (20 mL). Sodium (114 mg, 4.76 mmol, 60% in mineral oil) was added and stirred at room temperature for 22 hours. Water (20 ml) was added to the reaction mixture and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. Chromatographic purification on SiO ₂ (gradient 100: 0-90: 10, heptane- EtOAc) gave the title compound (708 mg, 47%) as a white powder.

Method A: LC-MS m / z = 277.85 [M + H] ⁺ ; RT = 1.39 minutes.

Step 2: Synthesis of 5-chloro-6H, 7H- [1,3] thiazolo [5,4-d] pyrimidine-7-one

7- (benzyloxy) -5-chloro- [1,3] thiazolo [5,4-d] pyrimidine (EV-AQ0259-002, 708 mg, 2.24 mmol) in 1 of 37% HCl-THF aqueous solution (10 mL). 1 Dissolved in a mixture and stirred at room temperature for 18 hours. The reaction mixture was filtered under vacuum, washed with THF and Et ₂ O, 5-chloro -6H, 7H- [1,3] thiazolo [5,4-d] pyrimidin-7-one (246 mg, 58% ) Was obtained as a pale yellow powder.

Method A: LC-MS m / z = 187.80 [M + H] ⁺ ; RT = 0.49 minutes.

Synthesis of Intermediate 16: 2,4-dichloro-7-methyl-7H-pyrrolo [2,3-d] pyrimidine

Sodium hydride (60% oily suspension, 383 mg) in THF (30 ml) solution of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (1.5 g, 7.98 mmol) at 0 ° C. 9.57 mmol) was added, and the mixture was stirred from 0 ° C. to room temperature for 20 minutes. Iodomethane (0.6 ml, 9.57 mmol) was added, and the mixture was stirred at room temperature for 3 hours.

The mixture was quenched by the addition of saturated ammonium chloride solution (20 mL). EtOAc was then added to form a precipitate. The precipitate was filtered and the filtrate was extracted with EtOAc (x2). The combined organic fractions were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give the title compound (1.65 g, 97.2%) as a yellow powder.

Method A: LC-MS m / z = 201.90, 203.90 [M + H] ⁺ ; RT = 1.21 minutes.

Examples 78-88

Examples 78-88 of Table 16 (Table 7) are carried out starting from the corresponding dichloropyrimidine or specific intermediate and coupling the intermediate acid with the appropriate amine using specific coupling conditions. Synthesis was performed according to the procedure described in Example 57.

Preparation Example 5

Preparation of Intermediate 17: 2-Hydrazinyl-3H, 4H, 5H, 6H, 7H-Cyclopentane [d] Pyrimidine-4-one (EV-AQ7134-001)

Step 1: Synthesis of 2-sulfanilidene-1H, 2H, 3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

Methyl 2-oxocyclopentanecarboxylate (17.83 mL, 143.65 mmol) in acetonitrile (150 mL) with thiourea (16.4 g, 215.47 mmol) followed by DBU (25.73 mL, 172.38 mmol). In addition, it was stirred at 80 ° C. for 24 hours. The reaction mixture was concentrated under reduced pressure and dissolved in water. The solution was acidified to pH 3/4 with 5M aqueous HCl, the resulting precipitate was collected, washed with water and diethyl ether and then dried under vacuum. The solid was further dried under vacuum at 40 ° C. overnight to give the title compound (17.81 g, 73.7%) as a beige powder.

Method A: LC-MS: m / z = 168.9 (M + H) ⁺ , RT = 0.2 to 0.45 minutes.

Step 2: Synthesis of 2- (methylsulfanyl) -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

2-Sulfanilidene-1H, 2H, 3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one (EV-AS7131-001, 17.81 g, 105.88 mmol) in water suspension (100 mL) NaOH (4.66 g, 116.46 mmol) was added, and iodomethane (7.25 mL, 116.46 mmol) was subsequently added dropwise. The reaction mixture was stirred at room temperature for 1.5 hours, then cooled to 5 ° C. and the resulting precipitate was collected by vacuum filtration. The solid was washed with ice-cold water (50 mL), water and diethyl ether (50 mL) and further dried under reduced pressure at 40 ° C. to give the title compound (17.78 g, 89.4%) as an off-white powder.

Method A: LC-MS: m / z = 182.9 (M + H) ⁺ ; RT = 0.89 minutes.

Step 3: Synthesis of 2-hydrazinyl-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

Hydrazine in a solution of 2- (methylsulfanyl) -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one (EV-AQ7133-001, 17.78 g, 97.56 mmol) in EtOH (30 mL). Hydrate (23.73 mL, 487.81 mmol) was added. The reaction mixture was stirred at 90 ° C. for 24 hours and then at 85 ° C. for an additional 7 hours. The cooled reaction mixture was filtered and washed with EtOH (15 mL) and water (10 mL) to give the title compound (13.1 g, 80.8%) as a white powder.

Method B: LC-MS: m / z = 166.9 (M + H) ⁺ , RT = 0.19 minutes.

Intermediate 18: 5-Methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-Cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid (Q-481, EV) -Preparation of AQ7139-001)

Step 1: 2- {5-Methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] Synthesis of pyrimidine-4-one

2-Hydradinyl-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one (EV-AQ7134-001, 19g, 114.33 mmol) in an ethanol (120 mL) solution of 2-[(dimethylamino ) Methylidene] -3-oxobutanoate methyl (EV-AL6988-001, 21.53 g, 125.77 mmol) followed by acetic acid (22.91 mL, 4.0.17 mmol). The reaction mixture was stirred at 50 ° C. for 3.5 hours. After 15 minutes, additional ethanol (170 mL) was added to maintain stirring. The reaction mixture was cooled and the solvent volume was reduced by about half. The resulting precipitate was collected and dried by vacuum filtration to give the title compound (21.84 g, 69.6%) as a beige powder.

Method B: LC-MS: m / z = 275.0 (M + H) ⁺ , RT = 0.98 minutes.

Step 2: 5-Methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid (Q-481, EV-) Synthesis of AQ7139-001)

Methyl 5-methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate (EV-AQ7137-001, 21. 84 g, 79.63 mmol) was suspended in 3: 2: 1 water / THF / methanol (300 mL) and a 2.5 M aqueous NaOH solution (191 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The organic matter was evacuated from the reaction mixture. The residue was acidified with a 5M HCl aqueous solution, the obtained precipitate was recovered, vacuum filtered at 45 ° C. for 5 days and dried to give the title compound (21.6 g, 100%) as a beige powder.

Method C: LC-MS: m / z = 261.1 (M + H) ⁺ , RT = 1.81 minutes.

Intermediate 19: Preparation of ± (syn) -2-methyl-4- (trifluoromethyl) piperidine hydrochloride

A MeOH (100 ml) solution of 2-methyl-4- (trifluoromethyl) pyridine (3 g, 18.62 mmol) was treated with a dioxane solution of 4M HCl (5.6 ml, 22.3 mmol) followed by platinum oxide (3 g, 22.3 mmol). iv) (253 mg, 1.12 mmol) was added and the resulting suspension was hydrogenated in a pressure vessel at 50 psi and room temperature for 4 hours. The catalyst was carefully removed by filtration over Celite and the filtrate was concentrated under vacuum to give the title compound (3.7 g, 99%) as a white solid.

Method A: LC-MS m / z = 168.0 [M + H] ⁺ ; RT = 0.21 minutes.

Intermediate 20: Synthesis of 2-methyl-4-phenylpiperidine-4-ol hydrochloride EV-AQ7159-002 used in (EV-AQ7163-003)

Step 1 : Synthesis of 4-hydroxy-2-methyl-4-phenylpiperidine-1-carboxylic acid tert-butyl structure using phenyllithium

L-boc-2-methyl-4-piperidinone (2.5 g, 11.72 mmol) in a solution of phenyllithium ( _{1.8 M, 7.16 mL, 12.89 mmol in Bu 2 O) in THF (15 mL) at −78 ° C.} ) Further THF solution (5 mL) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched by pouring into ice water. EtOAc (2 x 25 mL) was added and the product was extracted. The combined organics were dried (Na ₂ SO ₄ ), filtered and concentrated in vacuo. _{The crude residue was purified by SiO 2-} supported chromatography eluting with 0-100% EtOAc in heptane to give the title compound (2.97 g, 73.9%) as a yellow oil.

Method B: LC-MS: m / z = 192.0 (M-Boc) ⁺ , RT = 1.19 minutes.

Step 2: Synthesis of 2-methyl-4-phenylpiperidine-4-ol hydrochloride

Hydrochloric acid dioxane (4M, 6) in a dioxane (3 mL) solution of tert-butyl 4-hydroxy-2-methyl-4-phenylpiperidine-1-carboxylic acid (EV-AQ7159-002, 1.5 g, 5.15 mmol). .43 mL, 25.74) was added and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and redissolved in DCM and reconcentrated to give 1.22 g (83.3%) of the title compound as an orange rubber.

Method B: LC-MS: m / z = 192.0 (M + H) ⁺ , RT = 0.21 minutes.

Intermediate 21: 2- (4- {3-hydroxy-3-phenyl-8-azabicyclo [3.2.1] octane-8-carbonyl) -5-methyl-1H-pyrazole-1-yl) -3H, Synthesis of 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one.

2- (4- {3-Hydroxy-3-phenyl-8-azabicyclo [3.2.1] octane-8-carbonyl) -5-methyl-1H-pyrazole-1-yl) -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-4-one, 1-boc-2-methyl-4-piperidinone, 3-oxo-8-, according to the procedure described for Intermediate 21 (EV-AQ7161-001). Substitution with tert-butyl azabicyclo [3.2.1] octane-8-carboxylic acid gave the title compound (505 mg, 35%) as an off-white powder.

Method B: LC-MS: m / z = 203.9 (M + H) ⁺ , RT = 0.27 minutes.

Synthesis of Intermediate 22: 3-Phenyl-8-Azabicyclo [3.2.1] Octane Hydrochloride EV-AQ7185-002

Step 1: Synthesis of tert-butyl 3-phenyl-8-azabicyclo [3.2.1] octa-2-ene-8-carboxylic acid

3-oxo-8-azabicyclo [3.2.1] octane-8- in a solution of phenyllithium ( _{2.0 M in Bu 2} O, 3.66 mL, 7.32 mmol) in THF (15 mL) at −78 ° C. A solution of tert-butyl carboxylic acid (1.5 g, 6.66 mmol) in THF (5 mL) was added dropwise. The reaction was warmed to room temperature over 1 hour and stirred for an additional hour. One-third of the reaction mixture was removed for a similar chemical reaction and the remaining two-thirds of the reaction mixture was cooled to −78 ° C., methanesulfonyl chloride (1.03 mL, 13.32 mmol) followed by triethylamine. It was treated with (3.06 mL, 21.97 mmol). The reaction mixture was then warmed to room temperature and stirred overnight. The reaction mixture was cooled to −78 ° C. again, and methanesulfonyl chloride (2.06 mL, 26.64 mmol) and triethylamine (6.12 mL, 43.94 mmol) were further added. The reaction mixture was then warmed to room temperature and stirred for 3.5 hours. The reaction was diluted with water and extracted with EtOAc (3 x 20 mL). The combined organics were washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , and concentrated under vacuum. _{The crude residue was purified by SiO 2-} carrying chromatography eluting with heptane / EtOAc (0-100%) to give the title compound (480 mg, 36.8%) as an off-white solid.

The method ^{B: LC-MS: m /} z = 229.95 (M- t Bu) +, RT = 1.37 min.

Step 2: Synthesis of 3-Phenyl-8-Azabicyclo [3.2.1] Oct-2-ene Hydrochloride

In a dioxane (3 mL) solution of tert-butyl 3-phenyl-8-azabicyclo [3.2.1] octa-2-en-8-carboxylic acid (EV-AQ7180-002, 97%, 480 mg, 1.63 mmol) , HCl dioxane (4M, 2.04 mL, 8.16 mmol) was added and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum and redissolved in DCM and reconcentrated to give the title compound (355 mg, 93.2%) as an off-white powder.

Method B: LC-MS: m / z = 186.0 (M + H) ⁺ , RT = 0.79 minutes.

Step 3: Synthesis of 3-phenyl-8-azabicyclo [3.2.1] octane hydrochloride

3-Phenyl-8-azabicyclo [3.2.1] Oct-2-ene hydrochloride (EV-AQ7183-001, 355 mg, 1.92 mmol) was dissolved in MeOH: EtOAc (1: 1, 45 mL) and H. -cube Pd / C (10%) was hydrogenated at CatCart (1mL / min, 20bar, 60 ℃, controlled _{H 2} mode). The procedure was repeated at 40 bar, 60 ° C, and 60 bar, 60 ° C. The reaction mixture was concentrated under vacuum to give the title compound (305 mg, 76%) as an off-white powder.

Method B: LC-MS: m / z = 188.0 (M + H) ⁺ , RT = 0.74 minutes.

Synthesis of Intermediate 23: 4-Methoxy-4-phenylpiperidine-1-ium chloride EV-AQ8865-001

Step 1: Synthesis of tert-butyl-4-hydroxy-4-phenylpiperidine-1-carboxylic acid

A solution of phenyllithium ( _{1.8 M, 3.07 mL, 5.52 mmol in Bu 2} O) in THF (5 mL) into a solution of 1-Boc-4-piperidinone (1 g, 5.02 mmol) in THF (5 mL) -78. It was added dropwise at ° C. The reaction was warmed to room temperature and stirred for 4 hours. The reaction was quenched by pouring into ice water and extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried on nuclease ₄ and concentrated in vacuo. Elution with heptane / EtOAc (gradient 100: 0-20: 80) by SiO _2- supported chromatography and purification of the crude residue gave the title compound (1.095 g, 79%) as a yellow powder.

Method B: LC-MS: m / z = 177.9 (M-Boc) ⁺ , RT = 1.15 minutes.

Step 2: Synthesis of 4-methoxy-4-phenylpiperidine-1-carboxylate tert-butyl

4. In a stirred solution of 4-hydroxy-4-phenyl-piperidine-1-carboxylic acid tert-butyl ester (1.08 g, 3.91 mmol) in dry THF (25 mL), NaH (60% in oil, 0.17 g, 4. 30 mmol) was added, and the mixture was stirred for 1 hour, methyl iodide (0.37 mL, 5.86 mmol) was added, and the mixture was stirred overnight. The mixture was reprocessed with NaH (60%, 0.17 g, 4.30 mmol) followed by methyl iodide (0.37 mL, 5.86 mmol) and stirred overnight. The mixture was reprocessed 3 times with NaH (60%, 0.17 g, 4.30 mmol), followed by methyl iodide (0.37 mL, 5.86 mmol) and stirred for 4 hours. Brine (40 mL) was added and the product was extracted with EtOAc (2 x 50 mL). The combined organic extracts were _{dried in nuclease 4} and concentrated under vacuum and chromatographically eluted with heptane / EtOAc (gradient 100: 0-85: 15) for purification and the title compound (610 mg, 54%). Was obtained as an off-white powder.

Method B: LC-MS: m / z = 192.02 (M-Boc) ⁺ , RT = 1.30 minutes.

Step 3: Synthesis of 4-Methoxy-4-phenylpiperidine-1-ium chloride

4-Methoxy-4-phenylpiperidine-1-carboxylate (603 mg, 2.07 mmol) was dissolved in HCl dioxane (4M, 6 mL, 24.0 mmol) and stirred overnight at room temperature. The reaction mixture was concentrated under vacuum and triturated with ether to give the title compound (391 mg, 83%) as a colorless powder.

Method B: LC-MS: m / z = 191.9 (M + H) ⁺ , RT = 0.64 minutes.

Synthesis of Intermediate 24: 4- (2,2,2-trifluoroethoxy) piperidine

Step 1: Synthesis of 4- (2,2,2-trifluoroethoxy) pyridine

4-Chloropyridine hydrochloride (1 g, 6.67 mmol) in a solution of 2,2,2-trifluoroethanol (0.96 mL, 13.33 mmol) and NaH (60% in oil, 533.26 mg, 13.33 mmol). ) Anhydrous DMSO (20 mL) was added. The reaction mixture was stirred at 0 ° C. to room temperature overnight. Water (10 mL) was added and the product was extracted with DCM (2 x 50 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over Na ₂ SO ₄ , filtered, concentrated in vacuo and yellowish brown title compound (510 mg, 38.9%). Got

Method B: LC-MS: m / z = 178.0 (M + H) ⁺ , RT = 0.31 minutes.

Step 2: Synthesis of 4- (2,2,2-trifluoroethoxy) piperidine

4- (2,2,2-trifluoroethoxy) pyridine (EV-AQ7197-001, 510 mg, 2.88 mmol) was dissolved in EtOH: acetic acid (3: 1, 60 mL) in 5% Rh / C cat cart. It was subjected to H-cube hydrogenation (1 ml / min, 90 bar, 80 ° C.). The reaction mixture was concentrated under vacuum to give the title compound (104 mg, 11.9%) as a tan solid.

Method B: LC-MS: m / z = 184.0 (M + H) ⁺ , RT = 0.21-0.33 minutes.

Intermediate 25: Synthesis of ± (syn) -4-methyl-2- (trifluoromethyl) piperidine hydrochloride

A solution of 4-methyl-2- (trifluoromethyl) pyridine (1 g, 6.21 mmol) in MeOH (20 ml), HCl (4 M in dioxane, 1.9 mL), followed by platinum oxide (iv) (85 mg, 0. 37 mmol) was added and the resulting suspension was hydrogenated in a pressure vessel at 50 psi and room temperature for 20 hours. Further, platinum oxide (iv) (85 mg, 0.37 mmol) was added together with AcOH (10 ml), and hydrogenation was continued for 20 hours.

The catalyst was removed by filtration through Celite, the filtrate was evaporated under vacuum and the residue was pulverized with ether to give the title compound (460 mg, 36%) as a white solid.

Method B: LC-MS m / z = 167.95 [M + H] ⁺ ; RT = 0.18 minutes.

Example 89-141

Examples in Table 17 (Table 8) include intermediate 18 (5-methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-. 4-Carboxylic acid) was produced using Method 1 of reacting with a suitable amine using a specific coupling agent.

Example 142-145

The examples in Table 18 (Table 9) were prepared by chiral separation of the racemic compounds in Table 17 (Table 8). Stereochemistry was arbitrarily assigned.

Preparation Example 6 Direct cyclization of hydrazine

Preparation of Methyl Intermediate 26: 2-[(Dimethylamino) Methylidene] -3-oxobutanoate

Methyl 3-oxobutanoate (40 g, 0.34 mol) and 1,1-dimethoxy-N, N-dimethylmethaneamine (54.92 mL, 0.41 mol) were combined and stirred at 80 ° C. for 2 hours. The reaction mixture was concentrated under vacuum and the resulting oil was dried under vacuum for 24 hours to give the title compound (56.53 g, 86.3%) as a dark red solid.

^{1 1} HNMR (500 MHz, DMSO-d6) δ7.62 (s, 1H), 3.63 (s, 3H), 3.24-2.96 (m, 3H), 2.90-2.58 (m, 3H), 2.13 (s, 3H).

Preparation of Intermediate 27: 2-[(dimethylamino) methylidene] -1- (1,2,3,4-tetrahydroisoquinoline-2-yl) butane-1,3-dione (EV-AP2538-001)

Step 1: Synthesis of 1- (1,2,3,4-tetrahydroisoquinoline-2-yl) butane-1,3-dione

Methyl 3-oxobutate (12.76 mL, 118.25 mmol) and triethylamine (13.19 mL, 94.) in a solution of 1,2,3,4-tetrahydroisoquinoline (10.0 mL, 78.83 mmol) in toluene (80 mL). 6 mmol) was added, and the mixture was stirred at 105 ° C. for 15.5 hours. Water (15 mL) was added to the cooled reaction mixture and the organic phase was extracted. The organics were _{dried over Na 2} SO ₄ , filtered and concentrated in vacuo. The crude residue was _{purified by elution with 0-100% EtOAc heptane by SiO 2-} supported chromatography to give the title compound (12.8 g, 70.2%) as a viscous yellow oil.

Method A: LC-MS: m / z = 218.0 (M + H) ⁺ ; RT = 1.03 minutes.

Step 2: Synthesis of 2-[(dimethylamino) methylidene] -1- (1,2,3,4-tetrahydroisoquinoline-2-yl) butane-1,3-dione

1- (1,2,3,4-tetrahydroisoquinoline-2-yl) butane-1,3-dione (EV-AP2535-001, 2g, 9.21 mmol) and 1,1-dimethoxy-N, N-dimethyl Methaneamine (1.47 mL, 11.1 mmol) was combined and stirred at 80 ° C. for 15 hours. The reaction mixture was concentrated under vacuum to give the title compound (2.51 g, 96.1%) as a beige powder.

Method A: LC-MS: m / z = 273.0 (M + H) ⁺ ; RT = 0.99 minutes.

Intermediate 28: Preparation of (2E) -2-[(dimethylamino) methylidene] -1- [4- (trifluoromethyl) piperidine-1-yl] butane-1,3-dione (EV-AP2553-001)

The title compound was prepared in a manner similar to Intermediate EV-AP2535-001 starting with 4-trifluoromethylpiperidine hydrochloride (10.5 g, 55.4 mm) to give the title compound (13.4 g, 87%). Obtained as a dark orange powder.

Method A: LC-MS: m / z = 293.0 (M + H); RT = 0.97 minutes.

Preparation of Intermediate 29: 1- (1H-Pyrazole-4-carbonyl) -4- (Trifluoromethyl) Piperidine (EV-AQ8818-001)

T3P (50% in EtOAc, 10.5 mL, 17.) In a stirred solution of 1H-pyrazole-4-carboxylic acid (1.0 g, 8.92 mmol) and DIPEA (5.4 mL, 31.2 mmol) in THF (15 mL). 8 mmol) was added, and the mixture was stirred at room temperature for 5 minutes. 4- (Trifluoromethyl) piperidine hydrochloride (2.03 g, 10.7 mmol) was then added and the solution was stirred at room temperature overnight. The reaction mixture was cooled, partitioned into DCM (30 mL) and saturated NaHCO ₃ solution (40 mL), and the aqueous fraction was extracted with DCM (2 x 30 mL). The combined organic fractions were dried on nuclease ₄ and the solvent was removed in vacuo. _{The resulting oil was purified by SiO 2} supported chromatography on MeOH / DCM (gradient 100: 0-90: 10) to give the title compound (673 mg, 61%) as a yellow powder.

Method A: LC-MS m / z = 248.0 [M + H] ⁺ ; RT = 0.98 minutes.

Preparation of synthesis of intermediate 30: 6-chloro-2-hydrazinyl-3H, 4H-thieno [3,2-d] pyrimidine-4-one

Step 1: Synthesis of methyl 1H, 2H, 3H, 4H-thieno [3,2-d] pyrimidine-2,4-dione

A mixture of methyl 3-aminothiophene-2-carboxylate (3.5 g, 22.3 mmol) and urea (8.75 mL, 144.7 mmol) was heated at 180 ° C. for 5 hours. The mixture was cooled to ~ 90 ° C. and water (40 mL) was added. The mixture was stirred at room temperature overnight and the resulting precipitate was isolated by filtration to give the title compound (3.66 mg, 98%) as an off-white powder.

Method A: LC-MS m / z = 214.0 [M + H] ⁺ ; RT = 0.79 minutes.

Step 2: Synthesis of 6-nitro-1H, 2H, 3H, 4H-thieno [3,2-d] pyrimidine-2,4-dione

1H, 2H, 3H, 4H-thieno [3,2-d] pyrimidine-2,4-dione (EV-AP2346-001, 3.65 g, 21.7 mmol), smoked HNO ₃ (12 mL) and H ₂ SO ₄ (95%, 12 mL) was added little by little at 0 ° C. The reaction was warmed to room temperature and stirred for 1 hour. The precipitated solid was collected by filtration to give the title compound (1.28 g, 28%) as an orange powder.

Method A: LC-MS m / z = 214.0 [M + H] ⁺ ; RT = 0.79 minutes.

Step 3: Synthesis of 2,4,6-trichlorothieno [3,2-d] pyrimidine

6-Nitro-1H, 2H, 3H, 4H-Tieno [3,2-d] Pyrimidine-2,4-dione (EV-AP2349-001, 1.2g, 21.7 mmol) phenylphosphonic acid dichloride (5 mL, 35.3 mmol)) Stirring The suspension was stirred at 180 ° C. for 4 hours. The mixture was cooled to ~ 100 ° C. and slowly transferred to vigorously stirred ice / water (40 mL). The resulting suspension was stirred at room temperature for 30 minutes and then extracted with DCM (2 x 40 mL). The combined organic fractions _{were dried over Na 2} SO ₄ and concentrated under vacuum, SiO ₂ (0: 100-10: 90 MeOH-DCM) chromatography followed by additional SiO ₂ (0: 100-50: 50 EtOAc- Purification by heptane) chromatography gave the title compound (752 mg, 55%) as a colorless powder.

Method A: LC-MS m / z = 240.7 [M + H] ⁺ ; RT = 1.43 minutes.

Step 4: Synthesis of 2,6-dichloro-3H, 4H-thieno [3,2-d] pyrimidine-4-one

Add 1 M aqueous NaOH solution (16 mL, 16 mmol) to a stirred solution of 2,4,6-trichlorothieno [3,2-d] pyrimidine (EV-AP2352-001, 749 mg, 3.13 mmol) in THF (12 mL) at room temperature. Stirred overnight. The solution was acidified to pH-5 with 5M aqueous HCl and the resulting precipitate was isolated by filtration to give the title compound (400 mg, 58%) as a colorless powder.

Method A: LC-MS m / z = 220.8 [M + H] ⁺ ; RT = 1.02 minutes.

Step 5: Synthesis of 6-chloro-2-hydrazinyl-3H, 4H-thieno [3,2-d] pyrimidine-4-one

Hydrazine hydrate (hydrazine hydrate (5 mL) in a stirred solution of 2,6-dichloro-3H, 4H-thieno [3,2-d] pyrimidin-4-one (EV-AP2354-001, 361 mg, 1.63 mmol) in ethanol (5 mL). 199 μl (4.08 mmol) was added, and the mixture was stirred at 80 ° C. overnight. The reaction mixture was cooled, the precipitate was collected by filtration and the solid was washed with water to give the title compound (247 mg, 70%) as a yellow powder.

Method A: LC-MS m / z = 216.9 [M + H] ⁺ ; RT = 0.74 minutes.

Preparation of Intermediate 31: 5-Chloro-2-hydrazinyl-3,4-dihydropyrimidine-4-one

Step 1: Synthesis of 5-chloro-2-hydrazinyl-3,4-dihydropyrimidine-4-one

A 1M aqueous NaOH solution (35.4 mL, 35.4 mmol) was added to a solution of 2,4,5-trichloropyrimidine (5.00 g, 27.3 mmol) in THF (12 mL), and the mixture was stirred at room temperature for 3 days. The solution was acidified to pH-5 with 5M aqueous HCl and extracted with DCM (2 x 40 mL). The combined organic fractions _{were dried over Na 2} SO ₄ , concentrated under vacuum and triturated with 1: 4 DCM-heptane to give the title compound (2.33 g, 52%) as an orange powder. ..

Method A: LC-MS m / z = 164.8 [M + H] ⁺ ; RT = 0.38 minutes.

Step 2: Synthesis of 5-chloro-2-hydrazinyl-3,4-dihydropyrimidine-4-one

Add hydrazine hydrate (148 μL, 3.03 mmol) to a solution of 2,5-dichloro-3,4-dihydropyrimidine-4-one (EV-AP2350-001, 200 mg, 1.21 mmol) in ethanol (3 mL). , Stirred overnight at 50 ° C. The reaction mixture was cooled to room temperature and the resulting precipitate was isolated by filtration to give the title compound (88 mg, 45%) as an off-white powder.

Method A: LC-MS m / z = 160.9 [M + H] ⁺ ; RT = 0.17 minutes.

Preparation of Intermediate 32: 5-tert-butyl-2-hydrazinyl-3,4-dihydropyrimidine-4-one

Step 1: Synthesis of 2-formyl-3,3-ethyl dimethylbutanoate

_{TiCl 4} (52.01 ml, 52.01 mmol) and Et. in a solution of ethyl 3,3-dimethylbutanoate (5.814 ml, 34.67 mmol) and ethyl formate (8.366 ml, 104.01 mmol) in DCM (60 ml). ₃ N (11.61 mL, 83.21 mmol) was added under nitrogen at 0 ° C. and stirred at 0 ° C. to room temperature overnight. Water was added to the reaction mixture, which was then extracted with DCM (2 x 50 ml). The combined organic extracts were washed with brine, dried over Na ₂ SO ₄ , concentrated under reduced pressure and purified by column chromatography (100: 0-0: 100 heptane- EtOAc) to give the title compound (2. 72 mg, 42%) of free-flowing fluid orange oil was obtained.

^{1 1} H NMR (500 MHz, DMSO-d6) δ9.74 (d, J = 3.6 Hz, 1H), 4.21-4.10 (m, 2H), 3.07 (d, J = 3.6 Hz, 1H), 1.21 (t, J = 7.1Hz, 3H), 1.07 (s, 9H).

Step 2: Synthesis of 5-tert-butyl-2- (methylsulfanyl) -3,4,5,6-tetrahydropyrimidine-4-one

1M NaOH aqueous solution (534 μl, 0.534 mmol) and thiourea (534 μl, 0.534 mmol) in a water (2 ml) solution of ethyl 2-formyl-3,3-dimethylbutanoate (EV-AO7549-002, 92%, 100 mg, 0.534 mmol). 122 mg (1.603 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature and acidified to pH 2-3 with 1M aqueous HCl to give a white precipitate. The reaction mixture was filtered and washed with MeCN to give the title compound (72 mg, 73%) as a pearly white solid.

Method A: LC-MS m / z = 184.9 [M + H] ⁺ ; RT = 0.93 minutes.

Step 3: Synthesis of 3,6-dimethyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one

NaOH (97%, 286 mg, 6.925 mmol) was added to water (20 ml). After the sodium hydroxide has dissolved, 5-tert-butyl-2-sulfanilidene-1,2,3,4-tetrahydropyrimidine-4-one (EV-AO7576-001, 1.16 g, 6.295 mmol) is added. The mixture was stirred until dissolved. Iodomethane (435 μl, 6.925 mmol) was added dropwise and the mixture was stirred at room temperature overnight. The solid was filtered and washed with ice cold water (2 x 10 ml) to give the title compound (686 mg, 54%) as an off-white solid.

Method A: LC-MS m / z = 198.9 [M + H] ⁺ ; RT = 1.09 minutes.

Step 4: Synthesis of 5-tert-butyl-2-hydrazinyl-3,4-dihydropyrimidine-4-one

Hydrazine hydrate (1) in a solution of 5-tert-butyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one (EV-AO7579-001, 600 mg, 3.026 mmol) in pyridine (5 ml). .47 ml (30.26 mmol) was added, and the mixture was stirred at 100 ° C. overnight. The reaction mixture was concentrated under vacuum _{and milled with Et 2} O to give the title compound (331 mg, 60%) as an off-white powder.

Method A: LC-MS m / z = 183.0 [M + H] ⁺ ; RT = 0.40 minutes.

Preparation of Intermediate 33: 2-hydrazinyl-6- (trifluoromethyl) -3,4-dihydropyrimidine-4-one (EV-AO7596-001)

2-Hydradinyl-6- (trifluoromethyl) -3,4-dihydropyrimidine-4-one provides intermediate 32, 2-sulfanilidene-6- (trifluoromethyl) -1,2,3,4-tetrahydro. Prepared by a similar route substituted with pyrimidine-4-one to give the title compound (212 mg, 31%) as an off-white powder.

Method A: LC-MS m / z = 194.9 [M + H] ⁺ ; RT = 0.52 minutes.

Preparation of Intermediate 34: 6-Hydrazinyl-1H, 4H, 5H-Pyrazolo [3,4-d] Pyrimidine-4-one (EV-AQ7120-001)

Step 1: Synthesis of 4- (benzyloxy) -6-chloro-1H-pyrazolo [3,4-d] pyrimidine

Potassium t-butoxide (436.38 mg, 3.89 mmol) in a solution of benzyl alcohol (0.19 mL, 1.85 mmol) in dioxane (3 mL), followed by 4,6-dichloro-1H-pyrazolo [3,4-d]. Pyrimidine (350 mg, 1.85 mmol) was added at 0 ° C. The reaction mixture was warmed to room temperature over 15 minutes and then stirred for 21 hours. To the reaction mixture was quenched by addition of saturated aqueous _NH 4 Cl (2 mL), and extracted with EtOAc (2 × 5mL). The combined organic fractions _{were dried over Na 2} SO ₄ , filtered and concentrated under vacuum. The crude material was _{purified by elution with 0-50% EtOAc heptane by SiO 2-} supported chromatography to give the title compound (325 mg, 41.1%) as a white solid.

Method A: LC-MS: m / z = + 261.0, 262.9 (M + H) ⁺ ; RT = 1.28 minutes.

Step 2: Synthesis of 6-chloro-1H, 4H, 5H-pyrazolo [3,4-d] pyrimidine-4-one

4- (benzyloxy) -6-chloro-1H-pyrazolo [3,4-d] pyrimidine (EVA-AQ7113-003, 61%, 325 mg, 0.76 mmol) in THF (2.5 mL) solution of 4MHCl. A dioxane (1.9 mL) solution was added and stirred at room temperature for 1.5 hours. Concentrated HCl (2.5 mL) was then added and the reaction was stirred for an additional 2 hours. The resulting precipitate was collected, vacuum filtered and dried to give the title compound (128 mg, 98.7%) as a white powder.

Method A: LC-MS: m / z = + 170.9, 172.8 (M + H) ⁺ ; RT = 0.20

Step 3: Synthesis of 6-hydrazinyl-1H, 4H, 5H-pyrazolo [3,4-d] pyrimidine-4-one

Hydrazine hydrate (0) in a solution of 6-chloro-1H, 4H, 5H-pyrazolo [3,4-d] pyrimidin-4-one (EV-AQ7115-001, 128 mg, 0.75 mmol) in ethanol (2 mL). .18 mL (3.75 mmol) was added. The reaction vessel was sealed and the reaction mixture was irradiated with microwaves at 100 ° C. for 30 minutes. The reaction mixture was cooled, the resulting precipitate was collected and dried under vacuum to give the title compound (90 mg, 72.2%) as a white powder.

Method A: LC-MS: m / z = +166.9 (M + H) ⁺ ; RT = 0.17 minutes.

Preparation of Intermediate 35: 2-hydrazinyl-5,6-dimethyl-3,4-dihydropyrimidine-4-one (EV-AP2534-001)

Step 1: Synthesis of 5,6-dimethyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one

Sodium hydroxide (527.47 mg,) in a suspension of 5,6-dimethyl-2-sulfanilidene-1,2,3,4-tetrahydropyrimidine-4-one (2 g, 12.8 mmol) in water (15 mL). 13.19 mmol) followed by iodomethane (1 mL, 16 mmol) and stirred at room temperature overnight. The reaction mixture was cooled to 5 ° C. and the resulting precipitate was collected by vacuum filtration. The solid was washed with water and vacuum dried at 40 ° C. to give the title compound (1.67 g, 76%) as a white powder.

Method A: LC-MS m / z = 170.9 [M + H] ⁺ ; RT = 0.83 minutes.

Step 2: Synthesis of 2-hydrazinyl-5,6-dimethyl-3,4-dihydropyrimidine-4-one

Hydrazine hydrate (1.43 mL, 29.37 mmol) in 5,6-dimethyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one (EV-AB8059-001, 1 g, 5.87 mmol) ) Was added, and the mixture was stirred at 100 ° C. for 1.5 hours. The reaction was then left at room temperature throughout the weekend. An additional amount of hydrazine hydrate (1.43 mL, 29.37 mmol) was added, and the mixture was stirred at 100 ° C. for 1 hour. The reaction mixture was cooled to room temperature and ice-cold methanol (3 mL) was added. The resulting precipitate was collected by vacuum filtration and further washed with ice-cold methanol (5 mL). The solid was further dried under vacuum to give the title compound (618 mg, 68.2%) as a white powder.

Method A: LC-MS m / z = 154.9 [M + H] ⁺ ; RT = 0.17 minutes.

Preparation of Intermediate 36: 5-Chloro-6H, 7H- [1,3] thiazolo [4,5-d] pyrimidine-7-one (EV-AQ0249-001)

EV-AQ0249-001 was synthesized in a manner similar to the synthesis of EV-AQ0263-001 to give the title compound (190 mg, 56%) as a yellow powder.

Method A: LC-MS m / z = 187.85 [M + H] ⁺ ; RT = 0.37 minutes.

Intermediate 37a: Synthesis of 2-hydrazinyl-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

Step 1: Synthesis of 2-chloro-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

Sodium hydroxide (5M, 10.64 ml, 53.2 mmol) in a solution of 2,4-dichloropyrrolo [2,1-f] [1,2,4] triazine (2 g, 10.6 mmol) in THF (100 ml). Was added, and the reaction mixture was stirred at room temperature for 16 hours and further at 50 ° C. for 4 hours.

The yellow solution was cooled to room temperature, concentrated under vacuum and acidified (pH 3-4, 2M HCl). The resulting precipitate was collected by filtration, washed with water followed by ether and dried under vacuum to give the title compound (1.79 g, 99%) as a pale yellow powder.

Method B: LC-MS m / z = 160.0 [M + H] ⁺ ; RT = 0.79 minutes.

Step 2: Synthesis of 2-hydrazinyl-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

Hydrazine hydrate (43.04 μL, 0.88 mmol), 2-chloro-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one (100 mg, 0.59 mmol) After adding to the EtOH (2 ml) solution and stirring the reaction at room temperature for 18 hours, the suspension was heated at 80 ° C. for 40 hours.

Further, hydrazine hydrate (43.04 μL, 0.88 mmol) was added, and the reaction mixture was heated at 80 ° C. for 16 hours.

The yellow suspension was cooled to 4 ° C., the solid was collected by filtration, washed with cold water (~ 0.5 ml) and dried under vacuum to give the title compound (64 mg, 65%) as a yellow solid. ..

Method B: LC-MS m / z = 166.9 [M + H] ⁺ ; RT = 0.20 minutes.

2- [5-Methyl-4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3H, 4H-thieno [2,3-d] pyrimidine-4 -On preparation

2-Hydradinyl-3H, 4H-thieno [2,3-d] pyrimidine-4-one (formed in a manner similar to Intermediate 4) (EV-AP2372-001, 120 mg, 0.66 mmol) ethanol ( In a 3 mL) solution, 2-[(dimethylamino) methylidene] -1- (1,2,3,4-tetrahydroisoquinoline-2-yl) butane-1,3-dione (intermediate 27,90%, 199. 3 mg, 0.66 mmol) followed by acetic acid (0.13 mL, 2.31 mmol). The vessel was sealed and the reaction mixture was stirred at room temperature for 5 minutes and then heated at 80 ° C. for 5 hours. The reaction mixture was concentrated under vacuum. The crude residue was purified by elution with DCM of 0-10% methanol by _{SiO 2-supported chromatography.} This material was further purified by PREP-HPLC (Method G) to give the title compound (20.9 mg, 8.1%) as an off-white powder.

Method C: LC-MS m / z = 392.1 [M + H] ⁺ ; RT = 3.12 minutes.

Examples 146-156 and 157a

The examples in Table 19 (Table 10) were synthesized by cyclizing the corresponding hydrazine intermediates with intermediate 27 or 28 using the procedure described in Example 1.

Intermediate 37b: Synthesis of ethyl 2-formyl-3-oxopropanoate EV-AQ8817-001

Ethyl formate (8.5 mL, 105.7 mmol) was added to a stirring suspension of sodium hydride (60%, 1.68 g, 42.1 mmol) in THF (20 mL). The solution was cooled to 0 ° C., a solution of ethyl 3,3-diethoxypropanoate (4 g, 21.0 mmol) in THF (10 mL) was added dropwise over 30 minutes and the reaction mixture was stirred at room temperature overnight. A 2M aqueous HCl solution (30 mL) was added under ice cooling and the reaction was stirred at room temperature for 30 minutes. The reaction mixture was extracted with diethyl ether (2 x 50 mL), the combined organic extracts were _{dried in sulfonyl 4} and concentrated in vacuo to give the title compound (3.02 g, 99.7%) an amber liquid. Obtained as.

^{1 1} H NMR (250 MHz, chloroform-d) δ9.13 (s, 2H), 4.29 (q, J = 7.1 Hz, 2H), 1.37-1.28 (m, 3H).

Example 158a-6-methyl-2- [5-methyl-3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine- Preparation of 4-on Q-432 (EV-AQ0253-002)

Step 1: Synthesis of 3- [2- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) hydrazine-1-ylidene] methyl butanoate

EtOH of 2-hydrazinyl-6-methyl-3,4-dihydropyrimidine-4-one (Intermediate 1, EV-AO5744-001, 826 mg, 5.89 mmol) and methyl 3-oxobutanoate (763 μL, 7.07 mmol) The solution (20 ml) was heated under reflux for 3 hours. The reaction mixture was cooled to room temperature, concentrated in vacuo, triturated with EtOH, EtOH, followed by washed with Et ₂ O, to give the title compound (886 mg, 63%) as a pink solid.

Method A: LC-MS m / z = 239.00 [M + H] ⁺ ; RT = 0.71 minutes.

Step 2: Synthesis of 3-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylate

3- [2- (4-Methyl-6-oxo-1,6-dihydropyrimidine-2-yl) hydrazine-1-iriden] methyl butanoate (EV-AQ3804-001, 300 mg, 1.26 mmol) anhydrous DMF The (4 ml) solution was added dropwise with phosphorus trichloride (352 μl, 3.78 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 2 hours. The reaction mixture was quenched by the addition of water (1 ml), poured into crushed ice and left for 30 minutes. The solution was neutralized with 1 M aqueous NaOH solution and then concentrated under vacuum. The residue was dissolved in water (20 ml) and extracted with EtOAc (3 x 50 ml). The organic extracts were washed with brine, dried over magnesium sulfate, concentrated in vacuo and triturated with Et ₂ O, 3- methyl-1- (4-methyl-6-oxo-1,6 Methyl dihydropyrimidine-2-yl) -1H pyrazole-4-carboxylate (119 mg, 38%) was obtained as a pink solid.

Method A: LC-MS m / z = 249.00 [M + H] ⁺ ; RT = 1.01 minutes.

Step 3: Synthesis of 3-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylic acid

Methyl 3-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-4-carboxylate (EV-AQ3806-002, 120 mg, 0.44 mmol) A 3M aqueous NaOH solution (0.97 ml) was added to a THF (3 mL) solution, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to remove the organic solvent and the aqueous solution was acidified to pH 3 with 5M HCl aqueous solution. The precipitate filtered formed beige, and washed with _{H 2} O and Et ₂ O, 3- methyl-1- (4-methyl-6-oxo-1,6-dihydro-pyrimidin-2-yl ) -1H-Pyrazole-4-carboxylic acid (110 mg, 95%) was obtained as a beige powder.

Method A: LC-MS m / z = 235.0 [M + H] +; RT = 0.83 minutes.

Step 4: 6-Methyl-2-{3-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3,4-dihydropyrimidine-4-one Synthesis

THF of 3-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazol-4-carboxylic acid (EV-AQ0251-001, 35 mg, 0.15 mmol) In a (2 ml) suspension, DIPEA (91 μL, 0.52 mmol), T3P (50% in EtOAc) (176 μl, 0.30 mmol) and 4- (trifluoromethyl) piperidine hydrochloride (34 mg, 0.18 mmol). In addition, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum, redissolved in water (10 ml) and extracted with EtOAc (3 x 20 ml). The combined organic extracts were dried over sodium sulfate, concentrated under vacuum and _{purified by SiO 2-} supported chromatography (gradient 100: 0-80: 20, DCM-MeOH) to 6-methyl-2- {3. -Methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} -3,4-dihydropyrimidine-4-one (16 mg, 29%) off-white powder Obtained as.

Method C: LC-MS m / z = 370.2 [M + H] ⁺ ; RT = 2.40 minutes.

Preparation Example 7-Formation of product by cyclization to form substituted pyrazole

Intermediate 38: 2,4-Dichloro-7-methyl-7H-pyrrolo [2,3-d] Synthesis of pyrimidines

Sodium hydride (60% oily suspension, 383 mg) in THF (30 ml) solution of 2,4-dichloro-7H-pyrrolo [2,3-d] pyrimidine (1.5 g, 7.98 mmol) at 0 ° C. 9.57 mmol) was added, and the mixture was stirred from 0 ° C. to room temperature for 20 minutes. Iodomethane (0.6 ml, 9.57 mmol) was added, and the mixture was stirred at room temperature for 3 hours. The mixture was quenched by the addition of saturated ammonium chloride solution (20 mL). EtOAc was then added to form a precipitate. The precipitate was filtered and the filtrate was extracted with EtOAc (x2). The combined organic fractions were washed with water, dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give the title compound (1.65 g, 97.2%) as a yellow powder.

Method A: LC-MS m / z = 201.90, 203.90 [M + H] ⁺ ; RT = 1.21

Synthesis of Intermediate 39: 5-Chloro-6H, 7H- [1,3] thiazolo [5,4-d] pyrimidin-7-one

Step 1: Synthesis of 7- (benzyloxy) -5-chloro- [1,3] thiazolo [5,4-d] pyrimidi

Benzyl alcohol (495 μl, 4.76 mmol) and hydride at 0 ° C. in a solution of 5,7-dichloro- [1,3] thiazolo [5,4-d] pyrimidine (980 mg, 4.76 mmol) in THF (20 mL). Sodium (114 mg, 4.76 mmol, 60% in mineral oil) was added and stirred at room temperature for 22 hours. Water (20 ml) was added to the reaction mixture and the mixture was extracted with EtOAc (2 x 50 ml). The combined organic extracts were washed with brine, dried over sodium sulfate and concentrated under vacuum. Purification by SiO _2- supported chromatography (gradient 100: 0-90: 10, heptane- EtOAc) gave the title compound (708 mg, 47%) as a white powder.

Method A: LC-MS m / z = 277.85 [M + H] ⁺ ; RT = 1.39 minutes.

Step 2: Synthesis of 5-chloro-6H, 7H- [1,3] thiazolo [5,4-d] pyrimidine-7-one

7- (benzyloxy) -5-chloro- [1,3] thiazolo [5,4-d] pyrimidine (EV-AQ0259-002, 708 mg, 2.24 mmol) in 37% HCl-THF (10 mL) 1: 1 Dissolved in a mixed solution and stirred at room temperature for 18 hours. The reaction mixture was filtered under vacuum, washed with THF and Et ₂ O, to give the title compound (246 mg, 58%) as a pale yellow powder.

Method A: LC-MS m / z = 187.80 [M + H] ⁺ ; RT = 0.49 minutes.

Intermediate 40: Methyl-2-[(dimethylamino) methylidene] -4-methyl-3-oxopentanoic acid

To methyl 4-methyl-3-oxopentanoate (1.98 ml, 13.87 mmol), add 1,1-dimethoxy-N, N-dimethylmethaneamine (2.21 ml, 16.65 mmol) and bring the solution to 80 ° C. Stirred for 1 hour. The reaction mixture was concentrated under vacuum to give methyl-2-[(dimethylamino) methylidene] -4-methyl-3-oxopentanoic acid (2.76 g, 95%) as an orange oil.

Method A: LC-MS m / z = 200.0 [M + H] ⁺ ; RT = 1.00

Intermediate 41: Methyl-2-[(dimethylamino) methylidene] -4-methyl-3-oxopentanoic acid

To methyl 4-methyl-3-oxopentanoate (1.98 ml, 13.87 mmol), add 1,1-dimethoxy-N, N-dimethylmethaneamine (2.21 ml, 16.65 mmol) and bring the solution to 80 ° C. Stirred for 1 hour. The reaction mixture was concentrated under vacuum to give methyl-2-[(dimethylamino) methylidene] -4-methyl-3-oxopentanoic acid (2.76 g, 95%) as an orange oil.

Method A: LC-MS m / z = 200.0 [M + H] ⁺ ; RT = 1.00

Examples 157b, 158b and 159-180

The compounds in Table 20 (Table 11) were prepared by cyclizing the intermediate hydrazine with the appropriate enamine and then coupling with specific reagents.

Preparation Example 8: Formation of intermediate via SNAr

Examples 181-1- (1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carbonyl) -4-phenylpiperidine-4-carbotype Preparation of Nitrile EV-AR5394-002)

Step 1: Synthesis of 1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate ethyl

Ethyl 1H-pyrazole-4-carboxylate (2 ml) in a solution of 2-chloro-3H, 4H-thieno [3,2-d] pyrimidin-4-one (intermediate 9,647 mg, 3.47 mmol) in DMF (2 ml). Intermediate Y, 437 mg, 3.12 mmol), cesium carbonate (1.69 g, 5.20 mmol), L-proline (160 mg, 1.39 mmol) and copper (I) iodide (132 mg, 0.69 mmol) were added. .. The reaction mixture was then degassed and stirred at 120 ° C. overnight. The reaction mixture was concentrated under vacuum, 0.2 M aqueous EDTA solution (20 ml) and DCM (30 ml) were added and the mixture was stirred at room temperature overnight. The organic phase was separated and the aqueous phase was extracted with DCM (10 ml). The combined organic phases were washed with water, dried over sodium sulphate and concentrated under vacuum to give the title compound (559, 44%) as a beige powder.

Method B: LC-MS m / z = 290.95 [M + H] ⁺ ; RT = 1.02 minutes.

Step 2: Synthesis of 1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid. Intermediate 42

1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate ethylmethyl (EV-AR5386-001, 80%, 559 mg, 1. To a solution of 54 mmol) of THF (5 mL) and water (5 mL) was added 6M aqueous NaOH solution (2.57 mL) and the reaction mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum to remove the organic solvent and the aqueous mixture was acidified to pH 4 with 5M aqueous HCl. The reaction mixture was extracted with EtOAc (2 x 50 ml) and the combined organic extracts were dried over sodium sulfate and concentrated under vacuum to give the title compound (307 mg, 72%) as a light gray powder.

Method B: LC-MS m / z = 262.95 [M + H] ⁺ ; RT = 0.82 minutes.

Step 3: 1- (1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-4-carbonyl) -4-phenylpiperidine-4-carbonitrile Synthesis

1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazol-4-carboxylic acid (EV-AR5392-001, 80%, 52 mg, 0.159 mmol) Add DIPEA (69 μl, 0.40 mmol), T3P (50% in EtOAc) (234 μl, 0.40 mmol) and 4-phenylpiperidine-4-carbonitrile (33 mg, 0.17 mmol) to a solution of THF (2 ml). , The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and DCM (2 ml) and saturated NaHCO ₃ solution (1 ml) were added to the crude sample. The solution was then passed through a phase separator cartridge and concentrated under vacuum. Purification using an SCX cartridge and subsequently milling with MeOH gave the title compound (31 mg, 45%) as an off-white powder.

Method C: LC-MS m / z = 431.0 [M + H] ⁺ ; RT = 2.83 minutes.

Examples 182-184

The compounds in Table 21 (Table 12) were prepared by binding the appropriate amine to Intermediate 42 in the same manner as in Example 181.

Intermediate 43: 1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-Pyrazole-3-carboxylic acid synthesis

Step 1: Synthesis of 2-chloro-4-[(2-methoxyethoxy) methoxy] thieno [3,2-d] pyrimidine

2-Chloro-3H, 4H-thieno [3,2-d] pyrimidine-4-one (EV-AP2531-001, 750 mg, 4.02 mmol) and DIPEA (1.03 mL, 6.03 mmol) in THF (15 mL) 1- (Chloromethoxy) -2-methoxyethane (0.5 mL, 4.42 mmol) was added dropwise to the solution, and the mixture was stirred overnight at room temperature. EtOAc (50 mL) was added to the reaction mixture and washed with water (2 x 15 mL) and brine solution (15 mL). The organic fraction _{was dried over Na 2} SO ₄ and concentrated under vacuum to give the title compound (1.09, 87.9%) as a tan oil (as a mixture of N and O alkylation products). It was.

Method A: LC-MS: m / z = 274.9, 276.9 (M + H) ⁺ ; RT = 1.03, 1.19 minutes, A = 52% and 37%, respectively.

Step 2: Synthesis of 1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-3-carboxylate ethyl

Cesium carbonate (1.) in a solution of 2-chloro-4-[(2-methoxyethoxy) methoxy] thieno [3,2-d] pyrimidin (EV-AP2543-001, 902 mg, 3.28 mmol) in DMF (20 mL). 71 g) and ethyl 1H-pyrazole-5-carboxylate (506.13 mg, 3.61 mmol) were added, and the mixture was stirred at 120 ° C. for 30 minutes. The reaction mixture was cooled to 0 ° C., diluted with 1M aqueous HCl (45 mL) and stirred from 0 ° C. to room temperature for 30 minutes. The resulting precipitate was filtered under vacuum and dried to give the title compound (275 mg, 28%) as a light brown powder.

Method A: LC-MS: m / z = + 291.1 (M + H) ⁺ ; RT = 1.12 minutes.

Step 3: Synthesis of 1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-3-carboxylic acid intermediate 43

1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazole-3-carboxylate ethyl (EV-AP2547-001, 310 mg, 1.07 mmol), It was suspended in 2: 2: 1 THF / water / methanol (10 mL) and a 2.5 M NaOH aqueous solution (2.6 mL) was added. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under vacuum and the aqueous solution was acidified to pH 4 with 2M HCl aqueous solution. The resulting precipitate was filtered and dried under vacuum filtration to give the title compound (260 mg, 91%) as a light brown powder.

Method A: LC-MS: m / z = + 262.9 (M + H) ⁺ ; RT = 0.92 minutes.

Examples 185-2- [3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3H, 4H-thieno [3,2-d] pyrimidine-4 − On

1- {4-oxo-3H, 4H-thieno [3,2-d] pyrimidin-2-yl} -1H-pyrazol-3-carboxylic acid (intermediate 43) (EV-AP2548-001, 80 mg, 0. COMU (143.71 mg, 0.34 mmol), DIPEA (0.13 mL, 0.76 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.04 mL, 0) in a 31 mmol) DMF (1.0 mL) solution. .34 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the crude material was purified by PREP-HPLC (Method G) to give the title compound (28.7 mg, 24.9%) as a fluffy pale yellow solid.

Method C: LC-MS: m / z = + 378.1 (M + H) ⁺ ; RT = 2.98 minutes.

Example 186-187

Examples in Table 22 (Table 13) were prepared by coupling Intermediate 43 in the same manner as in Example 181.

Example 188-2-methyl-6- {3- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3,4-dihydropyrimidine-4-one (Q-) Preparation of 437, EV-AQ7121-003)

Step 1: Synthesis of 1- (2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl) -1H-pyrazole-3-carboxylate ethyl

In a microwave vessel, 6-chloro-2-methyl-3,4-dihydropyrimidine-4-one (450 mg, 3.11 mmol), ethyl 1H-pyrazol-5-carboxylate (610.74 mg, 4.36 mmol), A solution of cesium carbonate (1.72 g, 5.29 mmol), L-proline (143.36 mg, 1.25 mmol) and copper (I) iodide (118.57 mg, 0.62 mmol) in DMF (10 mL) was added. The reaction mixture was degassed by bubbling with nitrogen gas for 5 minutes and then irradiated in the microwave at 140 ° C. for 4 hours. Additional 6-chloro-2-methyl-3,4-dihydropyrimidine-4-one (150 mg, 1.04 mmol) was added and the reaction was irradiated at 140 ° C. for an additional 1.5 hours. EtOAc was added to the cooled reaction mixture and the organic layer was washed with brine (x2). The organics were _{dried in Na 2} SO ₄ , concentrated under vacuum _{, eluted by SiO 2} carrying chromatography with heptane of 0-100% EtOAc, followed by flushing with EtOAc in 50% methanol to purify the title compound. (294 mg, 11.4%) was obtained as a beige powder.

Method A: LC-MS: m / z = + 249.0 (M + H) ⁺ ; RT = 1.00 minutes.

Step 2: Synthesis of 1- (2-methyl-6-oxo-1,6-dihydropyrimidine-4-yl) -1H-pyrazole-3-carboxylic acid

1- (2-Methyl-6-oxo-1,6-dihydropyrimidine-4-yl) -1H-pyrazole-3-carboxylate ethyl (EV-AQ7119-001, 30%, 240 mg, 0.29 mmol) 2 It was suspended in 2: 1 THF / water / methanol (10 mL) and a 2.5 M aqueous NaOH solution (1.7 mL) was added. The reaction mixture was stirred at room temperature for 25 minutes. Organic matter was removed from the reaction mixture under vacuum. The residue was acidified with 2M aqueous HCl, the resulting precipitate was recovered and dried under vacuum filtration to give the title compound (55 mg, 86.1%) as a beige powder:

Method A: LC-MS: m / z = + 221.0 (M + H) ⁺ ; RT = 0.78.

Step 3: Synthesis of 2-methyl-6- {3- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3,4-dihydropyrimidine-4-one

1- (2-Methyl-6-oxo-1,6-dihydropyrimidine-4-yl) -1H-pyrazole-3-carboxylic acid (EV-AQ7123-001 75 mg, 0.34 mmol) in THF (2 mL) solution , DIPEA (0.20 mL, 1.19 mmol) and T3P 50% EtOAc (0.40 mL, 0.68 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes, and 4- (trifluoromethyl) piperidine-1-ium HCl (77.5 mg, 0.41 mmol) was added and stirred for an additional 14 hours. The reaction mixture was concentrated under vacuum and the crude residue was partitioned into water (1 mL) and DCM (5 mL). The organic phase was extracted, washed with saturated NaHCO ₃ solution (1 mL), water (1 mL) and brine solution (5 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude residue was purified by preparative HPLC (Method G) to give the title compound (43.2 mg, 35.7%) as an off-white powder.

Method C: LC-MS: m / z = + 356.2 (M + H) ⁺ ; RT = 2.32 minutes.

Synthesis of Intermediate 44 1- (4-Methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-3-carboxylic acid

Step 1: Synthesis of 2-chloro-4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine

NaH (60% in oil, 1.47 g, 36.8 mmol) in a stirred solution of (4-methoxyphenyl) methanol (3.39 g, 3.05 mL, 24.5 mmol) in THF (40 mL) at 0 ° C. added. After 1 hour, a solution of 2,4-dichloro-6-methylpyrimidine (4.0 g, 24.5 mmol) in THF (15 mL) was added dropwise and stirred at 0 ° C. to room temperature overnight. The reaction mixture was quenched by addition of saturated aqueous _NH 4 Cl (40 mL), and extracted with EtOAc (3 × 75mL). The combined organic fractions were washed with brine solution (40 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The resulting residue was purified by SiO _2- supported chromatography with a heptane / EtOAc eluate (gradient 100: 0-75: 25) to give the title compound (2.37 g, 36%) as a colorless crystalline solid.

Method A: LC-MS m / z = 256.0 [M + H] ⁺ ; RT = 1.39 minutes.

Step 2: Synthesis of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carboxylate ethyl

NaH (60%, 290 mg, 7.25 mmol) was added to a stirred solution of ethyl-1H-pyrazole-5-carboxylate (0.945 g, 6.74 mmol) at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes. 2-Chloro-4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine (1.70 g, 6.42 mmol) was then added and the reaction mixture was stirred at reflux for 4 days. The cooled reaction mixture was quenched with saturated aqueous _NH 4 Cl (40 mL), and extracted with EtOAc (2 × 40mL). The combined organic fractions were dried (Na ₂ SO ₄ ), concentrated in vacuo and eluted with heptane / EtOAc (gradient 100: 0-70: 30) by _{SiO 2 carrying chromatography to purify and title.} The compound (1.23 g, 52%) was obtained as a colorless powder.

Method A: LC-MS m / z = 369.1 [M + H] ⁺ ; RT = 1.43 minutes.

Step 3: Synthesis of ethyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-3-carboxylate

Stirred solution of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carboxylate (1.06 g, 2.73 mmol) in EtOAc (25 mL). the carbon-supported Pd (10%, 100mg) was added and the solution was exposed _H 2 (g) overnight under an atmosphere. The solution is filtered through Celite, washed with EtOAc, the filtrate is concentrated under vacuum and the residue is chromatographically eluted with heptane / EtOAc (gradient 100: 0-20: 80) for purification and the title compound ( 400 mg, 59%) was obtained as a colorless powder.

Method A: LC-MS m / z = 249.0 [M + H] ⁺ ; RT = 1.01 minutes.

Step 4: Synthesis of 1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-3-carboxylic acid

2: 1 THF / methanol stirred solution of ethyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazole-3-carboxylate (386 mg, 1.56 mmol) A 3M aqueous NaOH solution (3.1 mL) was added to (8 mL) and the reaction mixture was stirred at room temperature for 2 hours. The organic matter was removed under vacuum and the residue was acidified to pH 4/5 with 2M aqueous HCl and extracted with EtOAc (3 x 20 mL). The combined organics were _{dried over Na 2} SO ₄ and concentrated under vacuum to give the title compound (337 mg, 98%) as a colorless powder.

Method A: LC-MS m / z = 220.9 [M + H] ⁺ ; RT = 0.79 minutes.

Example 189-190

The examples in Table 23 (Table 14) were prepared by coupling Intermediate 44 with the appropriate amine using COMU as the coupling agent.

Examples 191-7- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -5H, 6H-imidazole [1,2-c] pyrimidine-5-one

Step 1: Synthesis of 7-chloro-5- (methylsulfanyl) imidazole [1,2-c] pyrimidine hydrochloride

Chloroacetaldehyde (50%, 1.63 mL, 12.8 mmol) was added to a stirred solution of 6-chloro-2- (methylsulfanyl) pyrimidine-4-amine (1.5 g, 8.54 mmol) in dioxane (4 mL). The mixture was stirred at 95 ° C. overnight. The reaction mixture was cooled in an ice bath and the resulting precipitate was filtered and washed with dioxane to give the title compound (1.41 g, 70%) as a colorless powder.

Method A: LC-MS m / z = 199.8 [M + H] ⁺ ; RT = 0.93 minutes

Step 2: Synthesis of 7-chloro-5H, 6H-imidazole [1,2-c] pyrimidine-5-one

A 2M KOH aqueous solution in a stirred solution of methyl 7-chloro-5- (methylsulfanyl) imidazole [1,2-c] pyrimidine hydrochloride (EV-AQ8808-001, 1.32g, 5.59 mmol) in methanol (4 mL). (10 mL, 20 mmol) was added and stirred under reflux overnight. The solution was cooled to room temperature and acidified to pH 5/6 with 5M aqueous HCl. The resulting precipitate was isolated by vacuum filtration to give the title compound (704 mg, 74%) as a tan powder.

Method A: LC-MS m / z = 169.9 [M + H] ⁺ ; RT = 0.23 minutes

Step 3: 7- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -5H, 6H-imidazole [1,2-c] pyrimidine-5-one

Stirring 7-chloro-5H, 6H-imidazole [1,2-c] pyrimidin-5-one (EV-AQ8809-001, 100 mg, 0.59 mmol) and cesium carbonate (288 mg, 0.89 mmol) in DMF (3 mL). To the solution is added 1- (1H-pyrazole-4-carbonyl) -4- (trifluoromethyl) piperidine (intermediate 29, EV-AQ8818-001, 175 mg, 0.71 mmol) and the reaction is 2 at 70 ° C. Stir for 3 hours at 100 ° C. Copper iodide (22 mg, 0.12 mmol) and L-proline (27 mg, 0.24 mmol) were added and the reaction was heated at 100 ° C. overnight. The reaction was transferred to microwave and heated at 150 ° C. for 6 hours. The reaction was cooled to room temperature, concentrated under vacuum and purified by PREP-HPLC (Method G) to give the title compound (70 mg, 31%) as a colorless powder.

Method C: LC-MS m / z = 379.2 [M + H] ⁺ ; RT = 2.00 minutes.

Example 192 Preparation of 2-chloro-7-fluoro-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

Q-525 (EV-AS3703-002)

Step 1: Synthesis of 2-chloro-7-fluoro-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

2,4-Dichloro-7-fluoropyrrolo [2,1-f] [1,2,4] Triazine (WO2011 / 88045A1, 2011) (446 mg, 2.16 mmol) in THF (20 ml) solution with 5 M NaOH aqueous solution (2.16 ml, 10.82 mmol) was added, and the mixture was stirred at room temperature for 22 hours. The reaction mixture was concentrated under vacuum and the residue was acidified to pH 5 with 2M aqueous HCl. The resulting precipitate was collected by vacuum filtration and washed with diethyl ether to give the title compound (283 mg, 35%) as an off-white powder.

Method B: LC-MS m / z = 187.9 [M + H] ⁺ ; RT = 0.86 minutes.

Step 2: 7-Fluoro-2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H-pyrrolo [2,1-f] [1 , 2, 4] Synthesis of triazine-4-one

The title compound was 2-chloro-7-fluoro-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one (140 mg, 0. (75 mmol) was purified by preparative HPLC [Method G] to 7-fluoro-2-{4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl}. -3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one (42 mg, 14%) was obtained as an off-white powder.

Method C: LC-MS m / z = 398.0 [M + H] ⁺ ; RT = 2.82 minutes.

Examples 193-2-{4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4 -Preparation of on (Q-526, EV-AR5391-002)

Step 1: Synthesis of 2-chloro-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

To a solution of 2,4-dichloro-5H, 6H, 7H-cyclopentane [d] pyrimidine (3 g, 15.87 mmol) in THF (15 mL) was added an aqueous 6M NaOH solution (10 equivalents, 26.45 ml) to prepare the reaction. The mixture was stirred at 50 ° C. for 48 hours. The reaction mixture was concentrated under vacuum to remove the organic solvent. The resulting aqueous solution was acidified to pH 4 with 5M HCl aqueous solution, extracted with EtOAc (2 x 50 ml), dried over sodium sulfate and concentrated under vacuum to give the title compound (2.09 g, 75%) a pale orange color. Obtained as a powder.

Method B: LC-MS m / z = 170.9 [M + H] ⁺ ; RT = 0.68 minutes.

Step 2: 2- {4- [4- (Trifluoromethyl) Piperidine-1-carbonyl] -1H-Pyrazole-1-yl} -3H, 4H, 5H, 6H, 7H-Cyclopentane [d] Pyrimidine-4- On synthesis

2- (1H-Pyrazole) in a solution of 2-chloro-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one (EV-AR535-002, 200 mg, 1.17 mmol) in DMF (2 ml). -4-carbonyl) -4- (trifluoromethyl) piperidine (EV-AQ8818-001, 319 mg, 1.29 mmol), cesium carbonate (573 mg, 1.76 mmol), L-proline (54 mg, 0.47 mmol) and iodine. Copper (I) (45 mg, 0.23 mmol) was added. The reaction mixture was degassed and stirred at 120 ° C. for 20 hours. The reaction mixture was concentrated under vacuum, then 0.2 M aqueous EDTA (20 ml) solution and DCM (30 ml) were added and the mixture was stirred at room temperature for 4 hours. The organic phase was separated and the aqueous phase was extracted with DCM (20 ml). The combined organic extracts were washed with water (10 ml), dried over sodium sulfate and concentrated under vacuum. Purification by PREP-HPLC (Method G) gave the title compound (140 mg, 31%) as a beige powder.

Method C: LC-MS m / z = 382.1 [M + H] ⁺ ; RT = 2.51 minutes

Example 194

The examples in Table 24 (Table 15) were prepared by the procedure described in Example 192, starting with 2,4-dichlorothioeno [3,2-d] pyrimidines instead.

Example 195-2-{4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H, 5H, 7H-flo [3,4-d] pyrimidine Preparation of -4-on (Q-453, EV-AQ8825-001)

Step 1: Synthesis of 2-chloro-3H, 4H, 5H, 7H-flo [3,4-d] pyrimidine-4-one

2,4-Dichloro-5H, 7H-flo [3,4-d] pyrimidine (EV-AQ8821-001, 1 g, 5.24 mmol) in THF (10 mL) agitated solution with 1 M NaOH aqueous solution (10.5 mL, 10.4 mmol). 5 mmol) was added and the mixture was stirred overnight at room temperature. The solution was acidified to pH 4/5 with acetic acid and extracted with DCM (3 x 30 mL). The combined organic extracts were dried on nuclease ₄ and concentrated in vacuo to give the title compound (890 mg, 99%) as an orange powder.

1H NMR (500MHz, DMSO-d6) δ4.88 (t, J = 3.3Hz, 2H), 4.81 (t, J = 3.3Hz, 2H).

Step 2: 2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H, 5H, 7H-flo [3,4-d] pyrimidine- 4-on synthesis

Stirring 7-chloro-5H, 6H-imidazole [1,2-c] pyrimidin-5-one (EV-AQ8821-001, 100 mg, 0.58 mmol) and cesium carbonate (283 mg, 0.87 mmol) in DMF (3 mL). To the solution was added 1- (1H-pyrazole-4-carbonyl) -4- (trifluoromethyl) piperidine (intermediate V, EV-AQ8818-001, 143 mg, 0.58 mmol) at 120 ° C. under microwave conditions. Was stirred for 5 hours. The reaction was cooled to room temperature, concentrated under vacuum and purified by PREP-HPLC (Method G) to give a colorless powder (59 mg, 27%).

Method C: LC-MS m / z = 382.2 [MH] ⁺ ; RT = 2.28 minutes.

Example 196-6-Methyl-2- [3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine-4-one ( Preparation of Q-308, EV-AN7470-001)

Step 1: Synthesis of 4-[(4-Methoxyphenyl) methoxy] -6-methyl-2- (methylsulfanyl) pyrimidine

6-Methyl-2- (methylsulfanyl) -3,4-dihydropyrimidine-4-one (EV-AO5743-001, 7 g, 44.8 mmol) of water (50 ml) and dioxane (100 ml) of intermediate 1 of step 1 ), NaOH (2.15 g, 53.8 mmol), followed by 1- (chloromethyl) -4-methoxybenzene (8.42 g, 53.8 mmol) was added, and the mixture was stirred at 50 ° C. for 1 hour. The reaction mixture is cooled to room temperature, the resulting precipitate is filtered under vacuum _{and eluted with Heptane / EtOAc (gradient 100: 0-0: 100) by SiO 2-} supported chromatography to purify and purify the title compound (gradient 100: 0: 0: 100). 1.54 g, 11.4%) was obtained as an oil.

Method A: LC-MS: m / z = + 277.0 (M + H) ⁺ ; RT = 1.40 minutes.

Step 2: Synthesis of 2-Methanesulfonyl-4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine

4-[(4-Methoxyphenyl) methoxy] -6-methyl-2- (methylsulfanyl) pyrimidine (EV-AN0083-002, 1.5 g, 5.43 mmol) in a DCM (15 mL) solution at 0 ° C. nitrogen. Under, mCPBA (75%, 2.50 g, 10.86 mmol) was added and stirred at room temperature for 1 hour. The reaction was diluted with chloroform (50 mL), mCPBA (200 mg, 0.87 mmol) was further added, and the reaction was stirred at room temperature for an additional hour. A 0.5 M aqueous sodium thiosulfate solution (20 mL) was added to quench the reaction. The organic layer is extracted, washed with saturated NaHCO ₃ solution (3 x 20 mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give the title compound (1.64 g, 104%) a pale yellow oil. Obtained as.

Method A: LC-MS: m / z = + 331.1 (M + Na) ⁺ ; RT = 1.23 minutes.

Step 3: Synthesis of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carboxylate ethyl

NaH (60% in oil, 31.13 mg, 0.78 mmol) was added to a solution of 1H-pyrazole-5-carboxylic acid ethyl (95.44 mg, 0.68 mmol) in DMF (5 mL) at 0 ° C. To room temperature for 30 minutes. Add a solution of 2-methanesulfonyl-4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine (EV-AO5710-002, 200 mg, 0.65 mmol) in DMF (5 mL) and add the reaction mixture at room temperature. The mixture was stirred for 5 hours. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic fractions were washed with water (3 x 10 mL) and brine solution (10 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. Purification by elution with heptane / EtOAc (gradient 100: 0-0: 100) by SiO _2- supported chromatography gave the title compound (154 mg, 62.5%) as a clear oil.

Method A: LC-MS: m / z = 391.1 (M + Na) ⁺ ; RT = 1.43.

Step 4: Synthesis of Intermediate 46 1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carboxylic acid

1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carboxylate ethyl (EV-AN7466-001, 125 mg, 0.34 mmol) 2: Suspended in 2: 1 THF / water / methanol (7.5 mL) and added 2.5 M aqueous NaOH solution (0.81 mL). The reaction mixture was stirred at room temperature for 30 minutes. The organic matter was removed in vacuo and the aqueous solution was acidified with a 2M HCl aqueous solution. The resulting precipitate was collected and dried under vacuum filtration. The filtrate was then extracted with EtOAc (2 x 10 mL), the combined extracts were _{dried over Na 2} SO ₄ , concentrated under vacuum and combined with the precipitate as the title compound (115 mg, 93) as an off-white powder. 0.6%) was obtained.

Method A: LC-MS: m / z = 363.1 (M + Na) ⁺ ; RT = 1.24 minutes.

Step 5: 2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carbonyl) -1,2,3,4-tetrahydroisoquinoline Synthesis of

DMF (1) of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazol-3-carboxylic acid (EV-AN7466-001, 115 mg, 0.34 mmol) To the solution (.5 mL), COMU (159.18 mg, 0.37 mmol), DIPEA (0.14 mL, 0.84 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.05 mL, 0.37 mmol) were added. Stirred overnight at room temperature. Ice water was added to the reaction mixture and the mixture was extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with saturated NaHCO ₃ solution (5 mL), brine solution (5 mL), dried over Na ₂ SO ₄ , and concentrated under vacuum. The title compound (119 mg, 70.4%) was obtained as an opaque gum by elution and purification with heptane / EtOAc (gradient 100: 0-0: 100) by _{SiO 2-supported chromatography.}

Method A: LC-MS: m / z = + 456.0 (M + H) ⁺ ; RT = 1.52 minutes.

Step 6: Synthesis of 6-methyl-2- [3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazol-1-yl] -3,4-dihydropyrimidine-4-one

2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-3-carbonyl) -1,2,3,4-tetrahydroisoquinoline (EV- TFA (0.16 mL) was added to a solution of AN7468-001, 89 mg, 0.2 mmol) in DCM (2 mL), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum, redissolved in DCM _{, washed with saturated NaHCO 3} solution, dried over Na ₂ SO ₄ and concentrated under vacuum. Purification by PREP-HPLC (Method G) method) followed by purification of the free base in saturated NaHCO ₃ solution to give the title compound (35.7 mg, 54.5%) as an off-white solid.

Method A: LC-MS: m / z = + 336.1 (M + H) ⁺ ; RT = 2.50.

Examples 197-198

The Examples in Table 25 (Table 16) were produced by coupling Intermediate 46 with the appropriate amine and then deprotecting in the same manner as in Example 197.

Examples 199-2- {3,5-dimethyl-4- [2-oxo-2- (pyrrolidin-1-yl) ethyl] -1H-pyrazole-1-yl} -6-methyl-3,4-dihydro Pyrrolidine-4-on EV-AN7461-001

The title compound (20.1 mg, 25.6%) is a HATU that couples ethyl 2- (3,5-dimethyl-1H-pyrazole-4-yl) acetate with pyrrolidine in the same manner as in Example 196. Was prepared by reacting with Step 2 of Example 196.

Method C: LC-MS: m / z = 316.2 (M + H) ⁺ ; RT = 2.05 minutes.

Example 200-6-Methyl-2- [5-methyl-3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine- Preparation of 4-on (Q-365, EV-AO7568-002)

Step 1: Synthesis of ethyl-1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -5-methyl-1H-pyrazole-carboxylate

2-Methanesulfonyl-4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine (Example 196 Step 2,500 mg, 1.622 mmol) in a DMF (10 mL) solution at 0 ° C. with NaH (60% oil). Medium) (60%, 78 mg, 1.946 mmol) was then added, followed by ethyl 5-methyl-1H-pyrazol-3-carboxylate (275 mg, 1.784 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched by the addition of water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with water (2 x 10 mL), brine solution (10 mL), dried over Na ₂ SO ₄ , concentrated under vacuum and SiO _2- supported chromatography (gradient 100: 0-0: 100). , Heptane- EtOAc) to give the title compound (406 mg, 65%) as a colorless oil.

Method A: LC-MS m / z = 383.1 [M + H] ⁺ ; RT = 1.45 minutes.

Step 2: Synthesis of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -5-methyl-1H-pyrazole-3-carboxylic acid

Ethyl-1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -5-methyl-1H-pyrazole-3-carboxylate (EV-AO7559-002, 406 mg, 1. To a 2: 2: 1 solution of THF / water / methanol (25 mL) of 062 mmol) was added aqueous 2.5 M NaOH solution (2.55 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was acidified to pH 6 with 2M HCl aqueous solution to give a white precipitate, which was filtered and dried under vacuum to give the title compound (340 mg, 90%) as a white powder. It was.

Method A: LC-MS m / z = 377.0 [M + H] ⁺ ; RT = 1.26 minutes.

Step 3: 2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -5-methyl-1H-pyrazole-3-carbonyl) -1,2,3 Synthesis of 4-tetrahydroisoquinoline

DMF of 5-methyl-1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-pyrazol-4-carboxylic acid (EV-AO7561-001, 150 mg, 0.423 mmol) COMU (199 mg, 0.466 mmol), DIPEA (181 μL, 1.058 mmol) and 1,2,3,4-tetrahydroisoquinoline (59 μL, 0.466 mmol) were added to the (2 ml) stirred solution. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to remove DMF and the crude residue was redissolved in water (50 ml). The reaction mixture was quenched by the addition of saturated sodium bicarbonate solution (20 ml) extracted with DCM (3 x 100 ml). The combined organic extracts were dried over sodium sulphate, concentrated under reduced pressure and _{purified by SiO 2-} supported chromatography (gradient 100: 0-100: heptane- EtOAc) to give the title compound (152 mg, 61%) a yellow color. Obtained as a viscous oil.

Method A: LC-MS m / z = 470.2 [M + H] ⁺ ; RT = 1.51 minutes.

Step 4: 6-Methyl-2- [5-methyl-3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine-4 -On synthesis

2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -5-methyl-1H-pyrazole-3-carbonyl) -1,2,3,4-tetrahydro Isoquinolin (EV-AO7563-002, 80%, 152 mg, 0.259 mmol) was dissolved in MeOH (10 ml) and H-cube conditions (1 ml / min, 1 bar, 50 ° C.) for Pd / C (10%) cat cartridges. , Full H2 mode). The solvent was then removed in vacuo and the residue was purified by grinding with MeCN to give the title compound (61 mg, 67%) as a white powder.

Method C: LC-MS m / z = 350.2 [M + H] ⁺ ; RT = 2.81 minutes

Example 201-6-Methyl-2- [5-methyl-3- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine- 4-on synthesis

The title compound was prepared in the same manner as in Example 200 using ethyl 4-methyl-1H-pyrazole-3-carboxylate instead of ethyl 5-methyl-1H-pyrazole-3-carboxylate.

Method C: LC-MS m / z = 350.2 [M + H] ⁺ ; RT = 2.81 minutes.

Examples 203-2-{4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H-pyrrolo [2,1-f] [1,2, 4] Preparation of triazine-4-one (Q-467, EV-AQ3851-002)

Step 1: Synthesis of 2-methanesulfonyl-3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one

2- (Methylsulfanyl) -3H, 4H-pyrrolo [2,1-f] [1,2,4] triazine-4-one (900 mg, 4.97 mmol) in AcOH (18 ml), hydrogen peroxide (35 ml) %, 8.7 ml, 0.1 mol) was added, and the obtained suspension was stirred at room temperature for 39 hours, during which the suspension was dissolved to form a precipitate. The precipitate was collected by vacuum filtration and washed with water followed by ether to give the title compound (950 mg, 88%) as a white solid.

Method B: LC-MS m / z = 213.9 [M + H] ⁺ ; RT = 0.73 minutes.

Step 2: 2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -3H, 4H-pyrrolo [2,1-f] [1,2,4 ] Synthesis of triazine-4-one

1- (1H-pyrazole-4-carbonyl) -4- (trifluoromethyl) piperidine (EV-AQ3840-001, 243.49 mg, 0.98 mmol), 2-methanesulfonyl-3H, 4H-pyrrolo [2, 1-f] [1,2,4] Triazine-4-one (200 mg, 0.94 mmol) and cesium carbonate (458.44 mg, 1.41 mmol) in DMF (4 ml) solution in addition to 175 under microwave conditions. The mixture was stirred at ° C. for 9 hours. The reaction mixture was concentrated under vacuum, redissolved in water and extracted with EtOAc (x2). The combined organic extracts were washed with brine, dried on nuclease ₄ and concentrated in vacuo to give clear gum. Purification by PREP-HPLC gave the title compound (37 mg, 10%) as a white solid. On the other hand, after the solid precipitates from aqueous solution, the solid is collected by vacuum filtration, washed with water, then washed with ether and dried overnight under vacuum to further batch (113 mg, 32%) of the title compound. Was obtained as a white solid.

Method C: LC-MS m / z = 380.0 [M + H] ⁺ ; RT = 2.66 minutes.

Example 204-6-Methyl-2-{1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl} -3, Preparation and preparation of 4-dihydropyrimidine-4-one (Q-291, EV-AN7447-001)
Example 205-4-methyl-6- {1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl} -1, 2-Dihydropyrimidine-2-one (Q-292, EV-AN7447-002)

Step 1: Synthesis of ethyl propanoate 3- [3,5-dimethyl-4- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-yl]

To a solution of pyrazole-4-boronic acid pinacol ester (500 mg, 2.58 mmol) in acetonitrile (10 mL) is added ethyl acrylate (0.42 mL, 3.87 mmol) followed by DBU (0.39 mL, 2.58 mmol). , Stirred at room temperature for 15.5 hours. The reaction mixture was concentrated under vacuum _{and purified by elution with heptane / EtOAc (gradient 100: 0-0: 100) by SiO 2} carrying chromatography to give the title compound (310 mg, 38%) as a clear oil. Obtained.

Method A: LC-MS: m / z = + 295.0 (M + H) ⁺ ; RT = 1.25 minutes.

Synthesis of 2-chloro-4-methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidine and 4-chloro-6-methyl-2- [2- (trimethylsilyl) ethoxy] pyrimidine

NaH (60% in oil, 490.74 mg, 12.27 mmol) was added to a stirred solution of 2- (trimethylsilyl) ethanol (3.5 mL) in THF (7 mL) at 0 ° C. The reaction mixture was warmed to room temperature for 15 minutes and then cooled to 0 ° C. again. A solution of 2,4-dichloro-6-methylpyrimidine (2 g, 12.27 mmol) in THF (8 mL) was added to the reaction mixture, and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was quenched by addition of saturated aqueous _NH 4 Cl (10 mL), and extracted with EtOAc (3 × 25mL). The combined organic extracts were washed with brine solution (10 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The title compound (2.21 g, 72.2%, 2.7: 1) was purified by elution with heptane / EtOAc (gradient 100: 0-50: 50) by _{SiO 2-supported chromatography as a white solid.} Positional isomer mixture) was obtained.

Method A: LC-MS: m / z = 216.9, 218.9 (M + H) ⁺ ; RT = 1.62 minutes.

Step 3: 3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazole-1-yl) ethyl propanoate and 3- (4- {6-- Synthesis of ethyl methyl-2- [2- (trimethylsilyl) ethoxy] pyrimidin-4-yl} -1H-pyrazole-1-yl) ethyl propanoate

2-Chloro-4-methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin (EV-AN7439-004, 185 mg, 0.76 mmol as a mixture of positional isomers), 3- [4- (tetramethyl-1, 3,2-Dioxaborolan-2-yl) -1H-pyrazol-1-yl] ethyl propanoate (EV-AN7436-002, 93%, 358.56 mg, 1.13 mmol) and CsF (172.2 mg, 1.13 mmol). _{), Pd (PPh 3} ) ₄ (87.33 mg, 0.08 mmol) was added to a solution of DME and ethanol (2: 1, 7.5 mL), and the mixture was stirred at 120 ° C. for 15 minutes under microwave conditions. The reaction mixture was cooled to room temperature and water (10 mL) and EtOAc (15 mL) were added. The organic fraction was extracted and the aqueous phase was further re-extracted with EtOAc (2 x 5 mL). The combined organics were washed with brine solution (5 mL), dried over Na ₂ SO ₄ and concentrated under vacuum. The title compound (285 mg, 81.1%, 2: 1 mixture of positional isomers) is transparent by elution and purification with heptane / EtOAc (gradient 100: 0-0: 100) by _{SiO 2-supported chromatography.} Obtained as an oil.

Method A: LC-MS: m / z = + 377.2 (M + H) ⁺ ; RT = 1.45 minutes.

Step 4: 3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazole-1-yl) propanoic acid and 3- (4- {6-methyl) Synthesis of -2- [2- (trimethylsilyl) ethoxy] pyrimidin-4-yl} -1H-pyrazole-1-yl) propanoic acid

3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazol-1-yl) ethyl propanoate (EV-AN7442-001, 285 mg (positional isomer) 0.76 mmol) was suspended in 2: 2: 1 THF / water / methanol (12.5 mL) and sodium hydroxide (147.13 mg, 3.68 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The organics were evacuated, the aqueous solution was acidified with 2M HCl aqueous solution and extracted with EtOAc (2 x 10 mL). The combined organics were _{dried over Na 2} SO ₄ and concentrated under vacuum to give the title compound (239 mg, 94%, 2: 1 position isomer mixture) as a colorless oil.

Method A: LC-MS: m / z = + 349.2 (M + H) ⁺ ; RT = 1.27 minutes.

Step 5: 3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazole-1-yl) -1- (1,2,3,4-) Tetrahydroisoquinoline-2-yl) propan-1-one and 3- (4- {6-methyl-2- [2- (trimethylsilyl) ethoxy] pyrimidin-4-yl} -1H-pyrazole-1-yl) -1 -Synthesis of (1,2,3,4-tetrahydroisoquinoline-2-yl) propan-1-one

3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazol-1-yl) propanoic acid (EV-AN7445-001, 120 mg (positional isomer) TBTU (278.63 mg, 0.87 mmol), DIPEA (0.12 mL, 0.72 mmol) and 1,2,3,4-tetrahydroisoquinoline (0) in a solution of 0.29 mmol) of DMF (4 mL). .06 mL, 0.43 mmol) was added and the mixture was stirred at room temperature for 15 hours. Ice water was added to the reaction mixture and the mixture was extracted with EtOAc (2 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over Na ₂ SO ₄ and concentrated under vacuum to give the title compound (162 mg, 87% as a mixture of positional isomers) as a colorless oil. ..

Method: LC-MS: m / z = + 464.2 (M + H) ⁺ ; RT = 1.47 minutes.

Step 6: 6-Methyl-2- {1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl} -3,4 -Dihydropyrimidine-4-one (Q-291, EV-AN7447-001) and 4-methyl-6- {1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) ) Propyl] -1H-pyrazole-4-yl} -1,2-dihydropyrimidine-2-one synthesis

3- (4- {4-Methyl-6- [2- (trimethylsilyl) ethoxy] pyrimidin-2-yl} -1H-pyrazole-1-yl) -1- (1,2,3,4-tetrahydroisoquinoline-) 2-Il) propan-1-one (EV-AN7446-001, 162 mg (as a mixture of positional isomers), 0.25 mmol) was dissolved in a DCM (4 mL) solution and TFA (1 mL) was added. The reaction mixture was stirred for 1.5 hours and then concentrated in vacuo. The crude residue was redissolved in DCM _{, washed with saturated NaHCO 3} solution, dried over Na ₂ SO ₄ and concentrated in vacuo to give the title compound as a mixture of positional isomers.

Isomeric 6-methyl-2-{1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl first eluted by purification by PREP-HPLC (Method G)) ] -1H-Pyrazole-4-yl} -3,4-dihydropyrimidine-4-one, Example 204 (Q-291, EV-AN7447-001) (20.2 mg, 22.1%) off-white powder Got as.

Method C: LC-MS: m / z = 364.2 (M + H) +; RT = 2.02

Second elution isomer 4-methyl-6- {1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl}- 1,2-Dihydropyrimidine-2-one Example 205 (Q-292, EV-AN7447-002) (12.2 mg, 12.5%) was isolated as a beige powder.

Example 206-6-Methyl-2-{1- [3-oxo-3- (pyrrolidin-1-yl) propyl] -1H-pyrazole-4-yl} -3,4-dihydropyrimidine-4-one ( Q-283, EV-AN7448-001)

The title compound was prepared in a manner similar to Example 204 to give the title compound (12.02 mg, 16.6%). Positional isomers could not be obtained with sufficient purity for testing.

Method C: LC-MS: m / z = 302.1 (M + H) ⁺ ; RT = 1.40

Example 207-2- [3,5-dimethyl-1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl}- 6-Methyl-3,4-dihydropyrimidine-4-one

The title compound was prepared in step 1 using 3,5-dimethyl-4- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole in a manner similar to Example 204. The title compound (21.9 mg, 38.5) was obtained.

Method C: LC-MS: m / z = 392.2 (M + H) ⁺ ; RT = 2.15

Example 208-4- {3,5-dimethyl-1- [3-oxo-3- (1,2,3,4-tetrahydroisoquinoline-2-yl) propyl] -1H-pyrazole-4-yl}- 6-Methyl-1,2-dihydropyrimidine-2-one (Q-285, EV-AN7453-002)

The title compound was prepared in step 1 using 3,5-dimethyl-4- (tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole in a manner similar to Example 204. The title compound (17.5 mg, 31.1) was obtained.

Method C: LC-MS: m / z = 392.2 (M + H) ⁺ ; RT = 1.82 minutes.

Examples 209-2- {3,5-dimethyl-1-[3-oxo-3- (pyrrolidin-1-yl) propyl] -1H-pyrazole-4-yl} -6-methyl-3,4-dihydro Pyrimidine-4-on

Coupling with pyrrolidine to prepare the title compound (20.1 mg, 25.6%) in a manner similar to Example 208.

Method C: LC-MS: m / z = 330.2 (M + H) ⁺ ; RT = 1.57 minutes.

Example 210-4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -1,2-dihydropyridine-2-one (Q-439, EV-AQ8815-001) and
Examples 211-4-methyl-6- {3-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -1,2-dihydropyridine-2-one (Q-440, EV-AQ8815-002)

Step 1: Synthesis of 6-chloro-2-hydrazinilidene-4-methyl-1,2-dihydropyridine

2,6-Dichloro-4-methylpyridine (102 mg, 0.63 mmol) was heated in hydrazine hydrate (1 mL) to ~ 110 ° C. for 3 hours. The solution was cooled to 0 ° C. and water (3 mL) was added. The resulting precipitate was isolated by filtration and washed with ice-cold water to give 6-chloro-2-hydrazinilidene-4-methyl-1,2-dihydropyridine (32 mg, 32%) as a pale yellow powder.

LC-MS m / z = 157.9 [M + H] ⁺ ; RT = 0.42 minutes.

Step 2: 2-Chloro-4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} pyridine and 2-chloro-4 Synthesis of -methyl-6- {3-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} pyridine

(2E) -2-[(dimethylamino) methylidene] -1- [4- (trifluoromethyl) piperidine-1-yl] butane-1,3-dione (EV-AP2353-001, 927 mg, 3.17 mmol) 2-Chloro-6-hydrazinyl-4-methylpyridine (500 mg, 3.17 mmol) was added to a stirred solution of EtOH (7 mL) and AcOH (635 μL, 11.1 mmol), and the reaction mixture was added to the reaction mixture at 80 ° C. overnight. Stirred. The reaction was cooled, the solvent was removed in vacuo, the resulting residue was partitioned between DCM (50 mL) and saturated NaHCO ₃ solution (60 mL), and the aqueous fraction was extracted with DCM (2 x 50 mL). Then, the combined organic fraction was dried (sulfonyl ₄ ) and concentrated in vacuum to 2-chloro-4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl. ] -1H-Pyrazole-1-yl} pyridine (1.08 g, 88%, a mixture of positional isomers) was obtained as a yellow powder.

LC-MS m / z = 387.1 [M + H] ⁺ ; RT = 1.41-1.43 minutes.

Step 3: 2- (benzyloxy) -4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} pyridine and 2- Synthesis of (benzyloxy) -4-methyl-6- {3-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} pyridine

2-Chloro-4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} pyridine (1.08 g, 2.79 mmol) To a stirred solution of dioxane (15 mL) of (crude mixture containing positional isomers), phenylmethanol (0.32 mL, 3.07 mmol) followed by t-BuOK (345 mg, 3.07 mmol) and the solution was added overnight. Heat refluxed. Further 1.1 equivalents of t-BuOK (345 mg, 3.07 mmol) and phenylmethanol (0.32 mL, 3.07 mmol) were added and the reaction was refluxed for an additional 3 hours. _{Saturated NH 4} Cl (50 mL) was added to the chilled solution, the mixture was extracted with EtOAc (2 x 80 mL), the combined organic fractions were dried on sulfonyl ₄ , the solvent was removed under vacuum and the resulting residue was obtained. Was purified by eluting with 0: 100-100: 0 EtOAc-Heptane by SiO _2- supported chromatography to give the title compound (593 mg, 82%, mixture of isomers) as an off-white powder.

LC-MS m / z = 459.2 [M + H] ⁺ ; RT = 1.56-1.60 minutes.

Step 4: 4-Methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -1,2-dihydropyridine-2-one and Synthesis of 4-methyl-6- {3-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} -1,2-dihydropyridine-2-one

2- (benzyloxy) -4-methyl-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} pyridine (530 mg, 1.16 mmol) in EtOAc (25 mL) solution of) a mixture of regioisomers, carbon supported Pd (10%, 100 mg) was added and the solution was exposed overnight under _H 2 (g) atmosphere. The solution is filtered through Celite washed with EtOAc, the filtrate is concentrated under reduced pressure and the residue is purified by PREP-HPLC (Method G) with 4-methyl-6- {5-methyl-4- [4- (trifluoro). Methyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} -1,2-dihydropyridine-2-one (42 mg, 10%) was obtained as a yellow powder and 4-methyl-6- {3-methyl- 4- [4- (Trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} -1,2-dihydropyridine-2-one (118 mg, 28%) was obtained as a yellow powder.

LC-MS m / z = 369.1 [M + H] ⁺ ; RT = 3.46 minutes.

LC-MS m / z = 369.1 [M + H] ⁺ ; RT = 3.67 minutes

Examples 212-4-methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -1,2-dihydropyridine-2-one, Q-460 , EV-AQ7135-001 Preparation

Step 1: Synthesis of 2-chloro-4-methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} pyridine

DMF of 1- (1H-pyrazol-4-carbonyl) -4- (trifluoromethyl) piperidine (EV-AQ8818-001, 91.55 mg, 0.37 mmol) and cesium carbonate (150.83 mg, 0.46 mmol) To the 2 mL) solution was added 2,6-dichloro-4-methylpyridine (50 mg, 0.31 mmol). The reaction mixture was stirred at 100 ° C. for 6 hours. The reaction mixture was concentrated under vacuum. The residue was diluted with water and extracted with EtOAc. The organics were washed with brine (x2), dried over Na ₂ SO ₄ and concentrated under vacuum. The crude residue was _{purified by elution with a solution of 0-100% EtOAc in heptane by SiO 2-} supported chromatography to give the title compound (45 mg, 39.1%) as an off-white powder.

Method A: LC-MS: m / z = 373.1 (M + H) ⁺ ; RT = 1.43 minutes.

Step 2: Synthesis of 2- (benzyloxy) -4-methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} pyridine

2-Chloro-4-methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} pyridine (EV-AQ7130-001, 45 mg, 0.12 mmol) To the dioxane solution (2 mL) was added benzyl alcohol (0.01 mL, 0.13 mmol) and potassium tert-butoxide (14.9 mg, 0.13 mmol), and the solution was heated at 90 ° C. for 4 hours. The reaction mixture was concentrated under vacuum _{and purified by elution with a solution of 0-100% EtOAc in heptane by SiO 2} carrying chromatography to give the title compound (72 mg, 33.5%).

Method A: LC-MS: m / z = 445.1 (M + H) ⁺ ; RT = 1.60 minutes.

Step 3: 4-Methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -1,2-dihydropyridine-2-one, Q-460, Synthesis of EV-AQ7135-001

Carbon-supported Pd (10%, 17 mg) 2- (benzyloxy) -4-methyl-6- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} pyridine (EV-AQ7129-002,72mg, 0.16mmol) in ethanol (5.0 mL) was added and the solution was stirred overnight under an _{H 2} atmosphere. Further carbon supported Pd (10%, 17mg) was added to the reaction was continued for an additional 5 hours stirring under _{a H 2} atmosphere. The solution was filtered through Celite and washed with EtOAc. The filtrate was concentrated under vacuum and the residue was purified by preparative HPLC (Method G) to give the title compound (8.2 mg, 14.3%) as an off-white powder.

Method C: LC-MS: m / z = 355.2 (M + H) ⁺ ; RT = 2.84 minutes.

Examples 213-6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -4- (trifluoromethyl) -1,2-dihydropyridine Preparation of -2-one

Step 1: Synthesis of 2-chloro-6-hydrazinyl-4- (trifluoromethyl) pyridine

Hydrazine hydrate (0.05 mL, 0.93 mmol) was added to a suspension of 2,6-dichloro-4- (trifluoromethyl) pyridine (100 mg, 0.46 mmol) in ethanol (2 mL) and the reaction vessel. Was sealed and heated at 40 ° C. for 1.5 hours and then at 70 ° C. for an additional 5.5 hours.

The solution was concentrated and the resulting solid was triturated with water to give the title compound (70 mg, 51.5%) as a light brown solid.

Method B: LC-MS: m / z = 211.9 (M + H) ⁺ ; RT = 0.91 minutes.

Step 2: Synthesis of 1- [6-chloro-4- (trifluoromethyl) pyridin-2-yl] -5-methyl-1H-pyrazole-4-carboxylate methyl

2-Chloro-6-hydrazinyl-4- (trifluoromethyl) pyridine (EV-AQ7141-001, 770 mg, 3.64 mmol) and 2-[(dimethylamino) methylidene] -3-oxobutanoate methyl (90%, 934) Acetic acid (0.729 mL, 12.74 mmol) was added to a solution of .57 mg, 4.91 mmol) in ethanol (22 mL), the reaction mixture was stirred at room temperature for 5 minutes and then heated at 50 ° C. for 1 hour. The mixture was concentrated under vacuum _{and purified by elution with a solution of 0-100% EtOAc in heptane by SiO 2} carrying chromatography to give the title compound (1.04 g, 88.5%) as a white powder.

Method B: LC-MS: m / z = 320.0 (M + H) ⁺ ; RT = 1.35 minutes.

Step 3: Synthesis of 1- [6- (benzyloxy) -4- (trifluoromethyl) pyridin-2-yl] -5-methyl-1H-pyrazole-4-carboxylate

Dioxane solution of 1- [6-chloro-4- (trifluoromethyl) pyridin-2-yl] -5-methyl-1H-pyrazole-4-carboxylate (EV-AQ7144-001, 600 mg, 1.88 mmol) To (10 mL) was added benzyl alcohol (0.21 mL, 2.06 mmol) and potassium tert-butoxide (231.68 mg, 2.06 mmol). The reaction mixture was stirred at 60 ° C. for 0.5 hours. The reaction mixture was concentrated under vacuum, diluted with water (10 mL) and extracted with EtOAc (25 mL). The organics were washed with brine, dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was purified by elution with a solution of 0-50% EtOAc in heptane by SiO2-supported chromatography to give the title compound (629 mg, 48%) (mixture with benzyl ester) as a clear oil.

Method B: LC-MS: m / z = 392.1 (M + H) ⁺ ; RT = 1.39 minutes.

Step 3: Synthesis of 5-methyl-1- [6-oxo-4- (trifluoromethyl) -1,6-dihydropyridine-2-yl] -1H-pyrazole-4-carboxylic acid

Carbon-bearing Pd (10%, 86 mg), 1- [6- (benzyloxy) -4- (trifluoromethyl) pyridin-2-yl] -5-methyl-1H-pyrazol-4-carboxylate (EV) -AQ7147-001, (mixture of benzyl ester) (629 mg, 1.61 mmol) ethyl acetate) (15.0 mL) was added to a stirred solution and the solution was stirred overnight under an _{H 2} atmosphere. The reaction mixture was filtered through Celite and washed with EtOAc. The filtrate was concentrated under vacuum _{and purified by elution with a solution of 0-100% EtOAc in heptane by SiO 2} carrying chromatography to give the title compound (107 mg, 21.6%) as an off-white powder.

Method B: LC-MS: m / z = 287.9 (M + H) ⁺ ; RT = 1.01

Step 4: 6- {5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazol-1-yl} -4- (trifluoromethyl) -1,2-dihydropyridine- Synthesis of 2-on, Q-466, EV-AQ7151-002

5-Methyl-1- [6-oxo-4- (trifluoromethyl) -1,6-dihydropyridine-2-yl] -1H-pyrazole-4-carboxylic acid (200 mg, 0.70 mmol) in THF (6. DIPEA (0.417 mL, 2.44 mmol) and T3P 50% EtOAc solution (0.821 ml, 1.39 mmol) were added to the 0 mL) solution. The reaction mixture was stirred at room temperature for 10 minutes, 4- (trifluoromethyl) piperidine-1-ium HCl (158.45 mg, 0.84 mmol) was added and the mixture was further stirred for 1 hour. The reaction mixture was concentrated under vacuum and then the crude residue was suspended in water (5 mL) and DCM (10 mL). Organic matter was extracted, then the aqueous phase was acidified to pH 3-4 and further extracted with DCM (5 mL). The combined organics were dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by the PREP-HPLC (Method G) method to give the title compound (19.1 mg, 6.4%) as an off-white powder.

Method C: LC-MS: m / z = 423.1 (M + H) ⁺ ; RT = 3.41

Examples 214-5-{4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -6H, 7H-thieno [2,3-c] pyridine-7-one Preparation of (Q-511, EV-AR5370-002)

Step 1: Synthesis of 5-chloro-7-[(4-methoxyphenyl) methoxy] -6H, 7H-thieno [2,3-c] pyridine

Cesium carbonate (341 mg, 1) in a solution of 5-chloro-7-[(4-methoxyphenyl) methoxy] thieno [2,3-c] pyridine (EV-AR5360-001, 200 mg, 0.65 mmol) in DMF (3 ml). .05 mmol) and 1- (1H-pyrazole-4-carbonyl) -4- (trifluoromethyl) piperidine (intermediate 29, EV-AQ8818-001, 178 mg, 0.719 mmol) were added and stirred at 140 ° C. for 5 hours. did. The reaction mixture was concentrated under vacuum and purified by PREP-HPLC (Method G) to give the title compound (56 mg, 44%) as an off-white powder.

Method B: LC-MS m / z = 185.8 [M + H] ⁺ ; RT = 0.86 minutes.

Step 2: 5- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} -6H, 7H-thieno [2,3-c] pyridine-7-one Synthetic

In a DMF solution (1 ml) of 5-chloro-7-[(4-methoxyphenyl) methoxy] -6H, 7H-thieno [2,3-c] pyridine (EV-AR5366-003, 56 mg, 0.302 mmol). 1- (1H-pyrazole-4-carbonyl) -4- (trifluoromethyl) piperidine (intermediate 29, 89 mg, 0.362 mmol), cesium carbonate (147 mg, 0.453 mmol), L-proline (14 mg, 0. 121 mmol) and copper (I) iodide (11 mg, 0.06 mmol) were added. The reaction mixture was then degassed and stirred at 140 ° C. for 16 hours. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 ml) and washed with brine (2 x 10 ml). The organic extract was dried over sodium sulphate, concentrated under vacuum and then purified by PREP-HPLC (Method G) and disrupted with MeCN to give the title compound (32 mg, 27%) as an off-white powder. It was.

Method C: LC-MS m / z = 397.1 [M + H] ⁺ ; RT = 2.67 minutes.

Examples 216-2- {5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-yl} -3H, 4H-thieno [3,2-d] pyrimidine-4 -On preparation

Step 1: Synthesis of 2- (ethoxycarbonyl) -1,3-thiazole-5-carboxylic acid

Ethyl amino (thioxo) acetate (1.60 g, 11.98 mmol) was added to a solution of bromopyruvic acid (2.0 g, 11.98 mmol) in anhydrous 1,4-dioxane (20 ml), and the mixture was stirred at 100 ° C. overnight. .. The reaction mixture was cooled to room temperature, basified with saturated NaHCO ₃ solution and extracted with EtOAc (2 x 20 ml). The organic extract was discarded. The aqueous extract was then acidified to pH 3/4 with 5M aqueous HCl and extracted with EtOAc (2 x 50 ml). The organic extract was dried over sodium sulphate and concentrated under vacuum to give the title compound (1.34 g, 54%) as an orange powder.

Method B: LC-MS m / z = 201.85 [M + H] ⁺ ; RT = 0.80 minutes.

Step 2: Synthesis of ethyl 5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxylate

DIPEA (2.9 ml, 16.6 mmol) in THF (15 ml) suspension of 2- (ethoxycarbonyl) -1,3-thiazole-5-carboxylic acid (EV-AS5405-001, 1.34 g, 6.66 mmol). 7 mmol), T3P (50% in EtOAc) (9.8 ml, 16.7 mmol) and 4- (trifluoromethyl) piperidine hydrochloride (1.39 g, 7.33 mmol) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and DCM (40 ml) and saturated NaHCO ₃ solution (20 ml) were added to the crude residue. The organic layer was extracted, washed with water (10 ml), dried over sodium sulfate and concentrated under vacuum to give the title compound (2.13 g, 75%) as a brown powder.

Method B: LC-MS m / z = 337.0 [M + H] +; RT = 1.09 minutes.

Step 3: Synthesis of 5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxylic acid

THF (10 mL) of ethyl 5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxylate (EV-AS5406-001, 79%, 2.10 g, 4.93 mmol) ) And water (5 ml), a 3M NaOH aqueous solution (8.22 ml) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to remove the organic solvent and the aqueous mixture was acidified to pH 2/3 with 5M aqueous HCl. The reaction mixture was extracted with EtOAc (2 x 50 ml) and the combined organic extracts were dried over sodium sulphate and concentrated in vacuo to give the title compound (874 mg, 40%) as a brown solid.

Method B: LC-MS m / z = 308.85 [M + H] ⁺ ; RT = 0.87 minutes.

Step 4: Synthesis of N- (2-carbamoylthiophene-3-yl) -5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxamide

In a solution of 5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxylic acid (EV-AS5407-001, 70%, 872 mg, 1.98 mmol) in THF (10 ml). , HATU (904 mg, 2.38 mmol), DIPEA (848 μl, 4.95 mmol) and 3-aminothiophene-2-carboxamide (310 mg, 2.18 mmol) were added and stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and redissolved in DCM (2 ml) and water (1 ml). The reaction mixture was filtered through a phase separator cartridge, concentrated under vacuum and chromatographically eluted with DCM / MeOH (gradient 100: 0-95: 5) for purification and the title compound (1.03 g, 88%). Was obtained as an orange oil.

Method B: LC-MS m / z = 432.90 [M + H] ⁺ ; RT = 1.09 minutes.

Step 5: 2- {5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-yl} -3H, 4H-thieno [3,2-d] pyrimidine-4- On synthesis

N- (2-carbamoylthiophene-3-yl) -5- [4- (trifluoromethyl) piperidine-1-carbonyl] -1,3-thiazole-2-carboxamide (EV-AS5408-002, 73%, 45 mg) , 0.076 mmol) MeOH (3 ml) solution, 1 M NaOH aqueous solution (380 μl, 0.38 mmol) was added and stirred at 70 ° C. for 2 hours. The reaction mixture was filtered to remove the precipitate, the filtrate was extracted with EtOAc (2 x 10 ml) and the organic extract was discarded. The aqueous extract was then acidified to pH 4/5 with 2M aqueous HCl. A white precipitate was formed, which was filtered, washed with water and purified by PREP-HPLC (Method G) to give the title compound (12 mg, 38%) as a white powder.

Method C: LC-MS m / z = 415.0 [M + H] ⁺ ; RT = 2.84 minutes.

Example 218-2- (5-methyl-4- {2,2,2-trifluoro-1- [4- (trifluoromethyl) piperidine-1-yl] ethyl} -1H-pyrazol-1-yl) Preparation of -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one (Q-503, EV-AQ7177-001)

Step 1: Synthesis of 2- [5-methyl-4- (trifluoroacetyl) -1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one

2-Hydradinyl-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one (EV-AQ7134-001, 150 mg, 0.9 mmol, intermediate 17) in THF (15 mL) solution in THF (15 mL), -10 3- (ethoxymethylidene) -1,1,1-trifluoropentane-2,4-dione (prepared using the procedure described in Journal of Fluorine Chemisty, 136, 38-42; 2012) at ° C. (EV). -AQ7167-001, 199.17 mg, 0.95 mmol) is added dropwise to a solution of THF (5 mL) over 20 minutes, and the mixture is stirred at −10 ° C. for 30 minutes and further at room temperature for 1 hour. The reaction mixture was concentrated under vacuum and dissolved in DCM. The organics were washed with brine, dried over _Na 2 SO _4, and concentrated in vacuo to give the title compound (310 mg, 92.4%) obtained as an orange powder, ketones and dehydrate in LC-MS Ionized as a mixture.

Method B: LC-MS m / z = 331.0 [M + H] ⁺ ; RT = 0.98 minutes; 313.0 [M + H] ⁺ ; RT = 1.14 minutes

Step 2: 2- [5-Methyl-4- (2,2,2-trifluoro-1-hydroxyethyl) -1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H-cyclopentane [d] ] Synthesis of pyrimidine-4-one

A _{solution of NaOH 4} (49.68 mg, 1.31 mmol) in MeOH (1 mL), an aqueous 1M NaOH solution (0.1 mL), followed by 2- [5-methyl-4- (trifluoroacetyl) -1H-pyrazole-1. -Il] -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-4-one (EV-AQ7169-001, 100 mg, 0.32 mmol) in MeOH (2 mL) solution was added and stirred at room temperature for 1 hour. did. The reaction mixture was quenched with water (~ 2 mL) and concentrated in vacuo. The residue was dissolved in EtOAc, washed with water (3 mL) and brine (3 mL), dried over _Na 2 SO _4, and concentrated in vacuo to give the title compound (95 mg, 94.4%) of an orange powder Obtained as.

Method B: LC-MS m / z = 315.0 [M + H] ⁺ ; RT = 0.99 minutes

Step 3: 2- (5-Methyl-4- {2,2,2-trifluoro-1- [4- (trifluoromethyl) piperidine-1-yl] ethyl} -1H-pyrazole-1-yl)- Synthesis of 3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one

2- [5-Methyl-4- (2,2,2-trifluoro-1-hydroxyethyl) -1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin- 4- on (EV-AQ7174-001,90mg, 0.29mmol) in DCM (3.5 mL) solution of at _{-10 ℃, Et 3 N (0.12mL} , 0.86mmol), followed by triflic anhydride (0.08 mL, 0.50 mmol) was added, and the mixture was stirred at −10 ° C. for 1 hour. The reaction mixture was washed with cold saturated NaHCO ₃ solution (3 mL) and water (3 mL). The organic extract was then _{dried over Na 2} SO ₄ and concentrated in vacuo. The residue was dissolved in THF (3 mL), cooled to 0 ° C., 4- (trifluoromethyl) piperidine-1-ium HCl (108.6 mg, 0.57 mmol) and potassium carbonate (118.74 mg, 0.86 mmol). The mixture was added to the stirring solution of No. 1 and stirred at 0 ° C. to room temperature for 15 hours. The reaction mixture was concentrated in vacuo and partitioned into DCM (2 mL) and water (1 mL). The organics were isolated using a phase separation cartridge, concentrated under vacuum and purified by PREP-HPLC (Method G) to give the title compound (21 mg, 16.3%) as a brown powder.

Method C: LC-MS m / z = 450.1 [M + H] ⁺ ; RT = 2.98 minutes

Example 219-3-methyl-5-{5-methyl-4- [4- (trifluoromethyl) piperidine-1-carbonyl] -1H-pyrazole-1-yl} phenol (Q-494, EV-AR5355- Preparation of 002)

Step 1: Synthesis of 2- [4- (hydroxymethyl) -5-methyl-1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-4-one

Methyl 5-methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylate (Step 1, EV of Intermediate 18) Lithium aluminum hydride (2.4 M THF solution, 1.82 mL, 4.35 mmol) was added dropwise to a solution of −AQ7137-001, 1 g, 3.65 mmol) in THF (20 mL) at 0 ° C. for 15 hours at room temperature. Stirred. The reaction mixture was quenched by the addition of water (15 mL), filtered through Celite and washed with methanol (15 mL). The filtrate was concentrated in vacuo to give the title compound (650 mg, 62%) as a pale yellow powder:

Method B: LC-MS m / z = 245 [M + H] ⁺ ; RT = 0.89 minutes

Step 2: Synthesis of 5-methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-4-carbaldehyde

2- [4- (Hydroxymethyl) -5-methyl-1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-4-one (EV-AQ7157-001, 650 mg) Manganese (IV) oxide (1.84 g, 21.12 mmol) was added to a solution of 2.64 mmol) of DCM (20 mL) and MeOH (10 mL), and the mixture was stirred at room temperature for 15 hours. Further, manganese oxide (IV) (1.84 g, 21.12 mmol) was added, and the mixture was stirred at room temperature for 6 hours. Further, manganese oxide (IV) (0.92 g, 10.56 mmol) was added, and the mixture was stirred at room temperature for 4 days. The reaction mixture was filtered through Celite, washed with DCM and MeOH, and the filtrate was concentrated in vacuo to give the title compound (558 mg, 68%) as a beige powder.

Method B: LC-MS m / z = 245 [M + H] ⁺ ; RT = 0.89 minutes

Step 3: 1-[(5-Methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazol-4-yl) methyl] piperidine -2-On synthesis

5-Methyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-4-carbaldehyde (EV-AQ7158-001, 80%, 80%, 90 mg, in anhydrous MeOH (3 mL) solution of 0.295 mmol), 5-amino-pentanoic acid ethyl hydrochloride (59 mg, 0.324 mmol) and _Et 3 N _{(164μl, 1.179mmol)} was added and stirred for 1 hour at room temperature .. _{NaBH 4} (13 mg, 0.354 mmol) was added to the reaction mixture, and the mixture was stirred at 45 ° C. for 16 hours. The reaction mixture was stirred at 50 ° C. for an additional 3 hours. The reaction mixture was cooled to room temperature and diluted with water (10 mL). The aqueous mixture was then acidified to pH 4 with 5M aqueous HCl and extracted with EtOAc (2 x 30 mL). The combined extracts were dried over sodium sulfate, concentrated under vacuum and purified by PREP-HPLC (Method G) to give the title compound (5 mg, 5%) as an off-white powder.

Method C: LC-MS m / z = 328.1 [M + H] ⁺ ; RT = 2.19 minutes.

Example 220:

Step 1: Synthesis of ethyl-1-{4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-4-carboxylate

NaH (60% in oil) (60%, 45 mg, 1.12 mmol) was added to a solution of 1H-pyrazole-4-carboxylate (143 mg, 1.022 mol) in DMF (5 mL) at 0 ° C. After warming the reaction mixture to room temperature for 30 minutes, 2-methanesulfonyl-4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine (Example 196 Step 2, EV-AO5710-002, 300 mg, 0) .97 mmol) was further added to DMF (1 mL). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was quenched by the addition of water (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic fractions were washed with brine (20 mL), dried (Na ₂ SO ₄ ) and concentrated under vacuum to give an opaque gum, which was _{subjected to SiO 2} carrying chromatography to 12-100% EtOAc. Elution with heptane solution and purification gave the title compound (266 mg, 66% yield) as a white powder.

Method A: LC-MS: m / z = + 391.10 (M + Na) ⁺ 1.41 minutes

Step 2: Synthesis of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-4-carboxylic acid

1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-4-carboxylate ethyl (EV-AN096-002 (266 mg, 0.64 mmol) in THF ( NaOH (3M, 1ml) was added to the (10ml) solution and the reaction was stirred at room temperature for 18 hours. Further NaOH (2.5M, 1.5ml) was added with MeOH (1ml) and the reaction was stirred for an additional 7 hours. The organic solvent was evaporated in vacuum and the aqueous phase was acidified to pH 1 with HCl (1M). The mixture was extracted with EtOAc (3 x 30 ml), washed with brine (2 x 20 ml) and dried (Na _2). SO ₄ ) was evaporated to give the title compound (199 mg, 64%) as a colorless gum.

Method A: LC-MS: m / z = + 363.0 (M + Na) ⁺ 1.20 minutes

Step 3: 2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-4-carbonyl) -1,2,3,4-tetrahydroisoquinoline Synthesis of

DMF (1 ml) of 1- {4-[(4-methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazol-4-carboxylic acid (EV-AN0090-001, 199 mg, 0.58 mmol) ) DIPEA (255 μl, 1.46 mmol) followed by TBTU (225 mg, 0.7 mmol) was added to the stirred solution. After stirring the reaction for 3 minutes, 1,2,3,4-tetrahydroisoquinoline (101 mg, 0.76 mmol) was added and then the reaction was placed under _{N 2.} The reaction was stirred for 16 hours, then quenched with water (20 ml) and extracted with DCM (3 x 30 ml). The organics were washed with brine (2 x 50 ml), dried (Na ₂ SO ₄ ), evaporated under vacuum and then azeotroped with heptane (2 x 50 ml) to remove residual DMF. The crude product was _{purified by elution with a 25-100% EtOAc / heptane gradient by SiO 2-} supported chromatography to give the title compound (220 mg, 72%) as a colorless gum.

Method C: LC-MS: m / z = 456.2 (M + H) ⁺ 1.40 minutes

Step 4: Synthesis of 6-methyl-2- [4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-pyrazole-1-yl] -3,4-dihydropyrimidine-4-one

2- (1- {4-[(4-Methoxyphenyl) methoxy] -6-methylpyrimidine-2-yl} -1H-pyrazole-4-carbonyl) -1,2,3,4-tetrahydroisoquinoline (EV- AO8800-002, 220 mg, 0.42 mmol) was dissolved in DCM (3 mL) and TFA (0.35 mL) was added. The reaction mixture was stirred for 1 hour and 30 minutes and then concentrated under vacuum. The crude residue was redissolved in DCM (30 ml), washed with sodium bicarbonate solution (saturated, 2 x 10 ml), dried (Na ₂ SO ₄ ) and concentrated under vacuum. The crude material was purified by preparative HPLC (Method G) to give the title compound (46 mg, 33%) as an off-white solid.

Method C: LC-MS: m / z = 336.1 (M + H) ⁺ 2.38 minutes

Example 221 6-Methyl-2- [4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-1,2,3-triazole-1-yl] -3,4-dihydropyrimidine Preparation of -4-on (Q-321, EV-A05730-002)

Step 1: Synthesis of 5-methyl-3H, 7H- [1,2,3,4] tetrazolo [1,5-a] pyrimidine-7-one

Sodium nitrite (0) in a solution of hydrazinyl-6-methyl-3,4-dihydropyrimidine-4-one (intermediate 1, EV-AN7477-001, 0.5 g, 3.6 mmol) in ice-cold acetic acid (3 mL). A solution of .37 g, 5.4 mmol) of water (0.4 mL) was added dropwise. The reaction mixture was stirred at 5 ° C. for 1 hour and then concentrated under vacuum. The residue was milled from water, filtered and dried in vacuo to give the title compound (335 mg, 59%) as a colorless solid.

Method A: LC-MS m / z = 152.1 [M + H] ⁺ ; RT = 0.24 minutes

Step 2: Synthesis of 1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-1,2,3-triazole-4-carboxylate

A solution of tert-butanol-water (1: 1) (4 mL) was degassed with a stream of nitrogen for 5 minutes, methyl-3H, 7H- [1,2,3,4] tetrazolo [1,5-a] pyrimidine-. 7-On (EV-AO5708-001, 200 mg, 1.32 mmol), copper (I) chloride (26 mg, 0.26 mmol) and methyl propionate (98%, 227 mg, 2.65 mmol) were added. The reaction mixture was stirred at 70 ° C. for 6 hours. The reaction mixture was diluted with _{CHCl 3 -10% IPA (5mL)} , washed with water (5mL) and brine (5 mL). The aqueous phase was reextracted with _{CHCl 3 -10% IPA (3 ×} 5mL), the combined organics were dried _(Na 2 _SO 4), and concentrated in vacuo. The title compound (183 mg, 53%) was obtained as a light-colored solid by eluting with 0 to 100% DCM / ammonia (7 M in methanol) by _{SiO 2-supported chromatography.}

Method A: LC-MS m / z = 235.9 [M + H] ⁺ ; RT = 0.90 minutes

Step 3: Synthesis of 1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-1,2,3-triazole-4-carboxylic acid

Methyl 1- (4-methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-1,2,3-triazole-4-carboxylate (EV-AO5726-001, 190 mg, 0.71 mmol) 1M KOH (1.25 mL, 1.25 mmol) was added to a solution of (3 mL) in methanol, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under vacuum and acidified with HCl (3M, 0.4 mL). The resulting precipitate was collected by filtration, washed with water (2 x 1 mL) and dried under vacuum to give the title compound (137 mg, 83%) as a light brown solid.

Method A: LC-MS m / z = 221.9 [M + H] ⁺ ; RT = 0.70 minutes.

Step 4: 6-Methyl-2- [4- (1,2,3,4-tetrahydroisoquinoline-2-carbonyl) -1H-1,2,3-triazole-1-yl] -3,4-dihydropyrimidine Synthesis of -4-on, Q-312, EV-AO5730-002

1- (4-Methyl-6-oxo-1,6-dihydropyrimidine-2-yl) -1H-1,2,3-triazole-4-carboxylic acid (EV-AO5728-001 (130 mg, 0.56 mmol)) DIPEA (233.05 μL, 1.4 mmol and COMU (98%, 268.42 mg, 0.61 mmol) was added to the solution of DMF (2 mL). The reaction mixture was stirred at room temperature for 2 minutes 1, 2, 3 , 4-Tetrahydroisoquinoline (98%, 83.48 mg, 0.61 mmol) was added and the reaction was stirred at room temperature for an additional 24 hours. Further COMU (98%, 268.42 mg, 0.61 mmol) and 1,2, 3,4-Tetrahydroisoquinoline (98%, 83.48 mg, 0.61 mmol) was added and the mixture was stirred at room temperature for 2 hours.

The reaction mixture was concentrated in vacuo and diluted with DCM (10 ml). The mixture was washed with HCl (1M 2 x 5 mL), water (5 mL) and brine (5 mL), dried (Na ₂ SO ₄ ) and concentrated in vacuo. The title compound (36 mg, 19%) was made into a colorless solid by eluting with DCM / methanol (0-2%) by _{SiO 2-supported chromatography to purify and then purifying with preparative HPLC (Method G).} Obtained.

Method C: LC-MS: m / z = 337.1 (M + H) ⁺ ; RT = 2.56 minutes

Examples 222-2-{5- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one Q Preparation of -472 (EV-AR5325-002)

Step 1: Preparation of 2- (5-bromopyridin-2-yl) -1H, 2H, 3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

Methyl 2-oxocyclopentane-1-carboxylate (1.1 eq, 569 μl, 4.584 mmol) in a solution of 5-bromopyridin-2-carboxymidamide (917 mg, 4.584 mmol) in dry MeOH (10 ml). Subsequently, NaOMe (5.4 M in MeOH) (1.1 eq, 934 μl, 5.043 mmol) was added, and the mixture was stirred at 60 ° C. for 20 hours. Methyl 2-oxocyclopentane-1-carboxylate (0.1 eq, 57 μl, 0.458 mmol) and NaOMe (5.4 M in MeOH) (0.1 eq, 85 μl, 0.458 mmol) were added. The mixture was stirred at 60 ° C. for 1 hour. The reaction mixture was concentrated in vacuo, the residue was redissolved in water and the solution was acidified to pH 3 with 2M aqueous HCl. The precipitate was vacuum filtered _{, washed with water and Et 2} O and dried to give the title compound (832 mg, 62%) as a creamy powder.

Method C: LC-MS m / z = 295.0 [M + H] ⁺ ; RT = 2.53 minutes.

Step 2: Preparation of 6- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} pyridin-3-carboxylate methyl

2- (5-Bromopyridine-2-yl) -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidine-4-one (EV-AR5317-001, 690 mg, 2.36 mmol) in THF (3 ml) In suspension, MeOH (3 ml), Mo (CO) ₆ (249 mg, 0.945 mmol), Pd (OAc) ₂ (53 mg, 0.236 mmol), tBu ₃ P (96 mg, 0.472 mmol) and DBU (705 μl). 4.724 mmol) was added, and the mixture was stirred at 120 ° C. overnight. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with saturated brine solution (10 mL), dried over Na ₂ SO ₄ , concentrated under vacuum and _{eluted by SiO 2} carrying chromatography (100: 0-95: 5, DCM-MeOH). The mixture was purified and disrupted with THF to give the title compound (109 mg, 17%) as an off-white powder.

Method C: LC-MS m / z = 272.1 [M + H] ⁺ ; RT = 2.27 minutes.

Step 3: Preparation of 5-cyclopropyl-1- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidin-2-yl} -1H-pyrazole-4-carboxylic acid

THF (EV-AR5321-002, 100 mg, 0.369 mmol) of methyl 6- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-2-yl} pyridin-3-carboxylate (EV-AR5321-002, 100 mg, 0.369 mmol) A 3M aqueous NaOH solution (737 μL, 2.21 mmol) was added to the 5 mL) solution, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under vacuum to remove the organic solvent and the aqueous mixture was acidified to pH 4 with 5M HCl aqueous solution; a white precipitate was formed. The reaction mixture was filtered under vacuum to give the title compound (65 mg, 53%) as an off-white powder.

Method B: LC-MS m / z = 258.0 [M + H] ⁺ ; RT = 0.84 minutes.

Step 4: Preparation of 2- {5- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

THF (3 mL) of 6- {4-oxo-3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-2-yl} pyridin-3-carboxylic acid (EV-AR5324-001, 64 mg, 0.249 mmol) ) Suspension was added DIPEA (130 μL, 0.746 mmol), T3P (50% in EtOAc) (440 μL, 0.746 mmol) and 4- (trifluoromethyl) piperidine hydrochloride (52 mg, 0.274 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and the recrystallization was redissolved in EtOAc (20 ml). The reaction mixture was then washed with water (10 ml), the organic extract was dried over sodium sulfate, concentrated under vacuum and purified by PREP-HPLC (Method G) to give the title compound (45 mg, 46) as a white powder. %) Was obtained.

Method C: LC-MS m / z = 393.2 [M + H] ⁺ ; RT = 2.65 minutes.

Examples 223-2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one Synthetic

Step 1: Preparation of 4-bromopyridin-2-carboxamidin hydrochloride

To a solution of 4-bromopyridin-2-carbonitrile (1 g, 5.46 mmol) in anhydrous MeOH (4 mL) was added a solution of sodium methoxide (0.5 M, 2.19 mL, 1.1 mmol) in MeOH and at room temperature 4 Stirred for hours. Ammonium chloride (0.32 g, 6 mmol) was added to the reaction mixture, and the mixture was stirred overnight at room temperature. The reaction was diluted with ether (10 mL) and stirred at room temperature for 30 minutes. The precipitate formed by filtration was washed with ether (2 x 4 mL) and dried under vacuum to give the title compound (967 mg, 74.8%) as a white powder.

Method B: LC-MS m / z = 199.8, 201.9 [M + H] ⁺ ; RT = 0.2 minutes.

Step 2: Synthesis of 2- (4-bromopyridin-2-yl) -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

Methyl 2-oxocyclopentane-1-carboxylate (609.16 μl, 4.91 mmol) and 4-bromopyridin-2-carboxamidine hydrochloride (0.97 g, 4.09 mmol) at room temperature in a nitrogen atmosphere with MeOH of NaOMe. It was dissolved in a solution (0.5 M, 9.8 mL, 4.9 mmol) and stirred at 60 ° C. overnight. The reaction mixture was concentrated under vacuum, the residue was redissolved in water and the solution was acidified to pH 3 with 2M aqueous HCl. The precipitate was collected by filtration, washed with water and diethyl ether and dried to give the title compound (783 mg, 65.6%) as a brown powder.

Method B: LC-MS m / z = 293.85 / 295 [M + H] ⁺ ; RT = 1.04 minutes.

Step 3: Synthesis of 2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4-one

2- (4-Bromopyridin-2-yl) -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-4-one (50 mg, 0.17 mmol) anhydrous 1,4-dioxane (2 mL) solution Under nitrogen, 4- (trifluoromethyl) piperidine-1-ium chloride (97.36 mg, 0.51 mmol), palladium acetate (2.88 mg, 0.01 mmol), (9,9-dimethyl-9H-). Xantene-4,5-diyl) bis (diphenylphosphane) (14.86 mg, 0.03 mmol), tripotassium phosphate (0.09 ml, 1.03 mmol), hexakis (oxomethylidene) molybdenum (18.07 mg, 0.03 mmol). 07 mmol) and N, N-dimethylpyridin-4-amine (41.82 mg, 0.34 mmol) were added. The reaction vessel was degassed, refilled with nitrogen (x3), sealed and heated at 140 ° C. for 45 minutes. The reaction mixture is diluted with EtOAc, concentrated on silica, _{eluted with SiO 2-} supported chromatography with 0-5% MeOH / DCM, then purified with a 5-15% rapid flush to give a brown rubbery substance. It was. The crude material is dissolved in IPA (0.3 mL), treated with an IPA solution of (2E) -but-2-endioic acid (0.01 mL, 0.09 mmol), stirred at room temperature for 4 minutes and diethyl ether (1 mL). ) Was added. The precipitate was slowly formed over 3 hours and left overnight. The precipitate was collected by filtration, washed with ether (2 x 1 mL) and dried under vacuum to give the title compound (9.7 mg, 14.2%) as a pale beige solid.

Method C: LC-MS m / z = 393.1 [M + H] ⁺ ; RT = 2.59 minutes

Example 224-2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H-thieno [3,2-d] Synthesis of pyrimidine-4-one

Step 1: Preparation of phenyl 2-cyanopyridine-4-carboxylate

4-Bromopyridine-2-carbonitrile (150 mg, 0.82 mmol), phenyl formate (0.12 ml, 1.07 mmol), palladium (II) acetate (5.52 mg, 0.02 mmol), tri-tert-butylphosphonium Tetrafluoroborate (28.54 mg, 0.1 mmol) and N, N-diethylethaneamine (0.15 ml, 1.07 mmol) were added to the microwave vessel under a nitrogen atmosphere. The reaction vessel was degassed, filled with nitrogen (x3), sealed and heated at 140 ° C. for 20 minutes under microwave irradiation. Palladium acetate (II) (5.52 mg, 0.02 mmol) and tri-tert-butylphosphonium tetrafluoroborate (28.54 mg, 0.1 mmol) were added further, the reaction vessel was degassed and nitrogen was added. It was refilled (x3), sealed and heated at 140 ° C. for 45 minutes under microwave irradiation. The resulting mixture was diluted with water (4 mL) and DCM (3 mL), stirred vigorously and the phases were separated using a phase separator cartridge. The aqueous phase was re-extracted with DCM (x2) and the organic extract was separated using a phase separator. The combined organic extracts were concentrated under vacuum _{and purified by elution with heptane / EtOAc (gradient 100: 0-55: 45) by SiO 2} carrying chromatography to give the title compound (94 mg, 94 mg, solidified pale yellow gum). 51%) was obtained.

Method B: LC-MS m / z = 224.9 [M + H] ⁺ ; RT = 1.11 minutes.

Step 2: Preparation of 4- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-carbonitrile

4- (Trifluoromethyl) piperidine-1-ium chloride (128.12 mg,) in a solution of phenyl 2-cyanopyridine-4-carboxylate (101 mg, 0.45 mmol) in anhydrous THF (1 mL) under a nitrogen atmosphere. 0.68 mmol), N, N-diethylethaneamine (0.13 ml, 0.9 mmol) and N, N-dimethylpyridin-4-amine (2.75 mg, 0.02 mmol) were added and the suspension was added to 45 ° C. Was stirred for 4-5 hours. The reaction mixture is diluted with DCM, concentrated on silica (1.5 g) and subjected to SiO _2- supported chromatography by heptane / EtOAc (gradient 100: 0-70: 30) followed by DCM / MeOH (gradient 100: 0). ~ 45: 55) was eluted and purified to give the title compound (102 mg, 80%) as a colorless glassy substance.

Method B: LC-MS m / z = 284.0 [M + H] ⁺ ; RT = 1.02 minutes

Step 3: Synthesis of 2- {4- [4- (trifluoromethyl) piperidine-1-carbonyl] pyridin-2-yl} -3H, 4H-thieno [3,2-d] pyrimidin-4-one

4- [4- (Trifluoromethyl) piperidine-1-carbonyl] pyridin-2-carbonitrile (0.1 g, 0.36 mmol) and methyl 3-aminothiophen-2-carboxylate (0.06 g, 0.4 mmol) ) To a solution of THF (2.5 mL) was added potassium tert-butoxide (0.04 g, 0.4 mmol) at 0 ° C. under a nitrogen atmosphere, and the mixture was stirred at 0 ° C. to room temperature for 3 hours. The reaction mixture was concentrated under vacuum, diluted with saturated ammonium chloride (5 mL) and water and stirred at room temperature. The mixture was extracted with DCM (x2), followed by EtOAc, and the combined organic extracts were _{dried over Na 2} SO ₄ and concentrated in vacuo. The crude residue was stirred in diethyl ether (9 mL) at room temperature for 30 minutes, the resulting solid was filtered, washed with diethyl ether (x2), dried under vacuum and the title compound (58 mg, 38.6). %) Was obtained as a white solid.

Method C: LC-MS m / z = 409.1 [M + H] ⁺ ; RT = 2.75 minutes

Examples 225-2- (4-{[4- (trifluoromethyl) piperidine-1-yl] sulfonyl} pyridin-2-yl) -3H, 4H, 5H, 6H, 7H-cyclopentane [d] pyrimidine-4 -On synthesis

In a pressure tube, palladium (II) acetate (0.01 g, 0.03 mmol), N, N, N-tributylbutane-1-aminium bromide (182 mg, 0.56 mmol), triphenylphosphine (20 mg, 0.08 mmol). , Sodium formate (77 mg, 1.13 mmol), 1,10-phenanthroline hydrate (1: 1) (0.02 g, 0.08 mmol), and dipotassium oxide sulfansulfonate (0.23 g, 1. 03 mmol) was vigorously stirred in anhydrous DMSO (3 mL) under nitrogen atmosphere and 2- (4-bromopyridine-2-yl) -3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidin-4- On (Example 223 Step 2) (0.15 g, 0.51 mmol) was added, the vessel was sealed and heated at 70 ° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with MeOH (5 mL) and stirred for 5-10 minutes. The mixture was filtered through a small pad of Celite®, washed with MeOH (3 x 2 mL), concentrated in vacuo and triturated with diethyl ether (2 x 4 mL). The resulting solid was azeotroped with toluene and cooled to 0 ° C., 4- (trifluoromethyl) piperidine-1-ium chloride (0.11 g, 0.56 mmol), DIPEA (223.59 μL, 1.28 mmol). ) And 1-chloropyrrolidine-2,5-dione (41.55 μL, 0.51 mmol) in a solution of DMF (1 mL) and stirred at room temperature for 72 hours. The reaction mixture was diluted with water (10 mL), extracted with EtOAc (3 x 25 mL) and the combined extracts washed with water (x 4) and brine. The organics were _{dried over Na 2} SO ₄ , concentrated in vacuo and triturated with ether. The solid was suspended in MeOH (~ 4-5 mL) and heated to dissolve. The solution was concentrated under vacuum and milled with ether to give the title compound (96 mg, 44%) as a pale yellow solid.

Method C: LC-MS m / z = 429.1 [M + H] ⁺ ; RT = 3.15 minutes

Example 226-2- [4- (Cyclopentyloxy) -1H-pyrazole-1-yl] -3H, 4H, 5H, 6H, 7H] -synthesis of cyclopenta [d] pyrimidin-4-one

2-Chloro-3H, 4H, 5H, 6H, 7H-cyclopenta [d] pyrimidine-4-one (Example 193 Step 1, 74 mg, 0.43 mmol) and 4- (cyclopentyloxy) -1H-pyrazole (85 mg, Cesium carbonate (434 mg, 1.33 mmol) was added to a solution of 0.46 mmol) of DMF (3 mL). The mixture was irradiated with microwaves at 170 ° C. for 1 hour. Under these conditions, after an additional hour, the cooled reaction mixture was diluted with HCl (1M 20 mL), extracted with EtOAc (20 mL), the organic fraction was dried (trimethyl ₄ ) and concentrated under vacuum. Purification by PERP-HPLC (Method G) gave the title compound (32 mg, 26%) as a colorless powder.

Method C: LC-MS m / z = 287.1 [M + H] ⁺ ; RT = 3.10 minutes

Example 227 Synthesis of butane nitrile hydrochloride (piperidin-4-yl) butane nitrile hydrochloride

Step 1: Synthesis of 4- (1-cyanopropyl) piperidine-1-carboxylate tert-butyl

A solution of 2.5 M n-BuLi in THF (0.28 mL, 0.7 mmol) was added to a solution of diisopropylamine (54 mg, 0.536 mmol) in THF (2 mL) at −78 ° C. The solution was stirred for 30 minutes and a solution of tert-butyl 4- (cyanomethyl) piperidine-1-carboxylate (100 mg, 0.446 mmol) was added dropwise at −78 ° C. The resulting solution was stirred for 1 hour and iodoethane (83.6 mg, 0.536 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated Na ₄ Cl (5 mL), extracted with EtOAc (30 mL x 2), the combined organics were _{dried over Na 2} SO ₄ and concentrated to give the product (110 mg, 98% yield). , This was used in the next step without purification.

LC-MS: m / z = 197 (M-55) ⁺ , RT = 1.70 minutes.

Step 2: Synthesis of 2- (piperidine-4-yl) butanenitrile hydrochloride

A solution of 4.0 M HCl in dioxane (2 mL) was added to a solution of tert-butyl 4- (1-cyanopropyl) piperidine-1-carboxylate (110 mg, 0.436 mmol) in DCM (2 mL). The solution was stirred at room temperature for 4 hours. The solvent of the reaction was then removed to give the product (85 mg, 99%) as a white solid.

LC-MS: m / z = 153 (M + H) ⁺

Example 228-4-Ethylpiperidin-4-Carbonitrile Hydrochloride Synthesis

Step 1: Synthesis of tert-butyl 4-cyano-4-ethylpiperidine-1-carboxylate

A solution of 2.5 M n-BuLi in THF (7.2 mL, 18 mmol) was added to a solution of diisopropylamine (1.818 g, 18 mmol) in THF (20 mL) at −78 ° C. The solution was stirred for 30 minutes and then added dropwise to a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (3.15 g, 15 mmol) in THF (40 mL) at −78 ° C. The resulting solution was stirred for 1 hour and iodoethane (83.6 mg, 0.536 mmol) was added. The reaction mixture was stirred overnight. The reaction was quenched with saturated NH ₄ Cl (10 mL) and water (20 mL), extracted with EtOAc (50 mL × 2), the combined organics were _{dried over Na 2} SO ₄ and concentrated to give the product (3. 4 g, yield 95.2%), which was used in the next step without purification.

LC-MS: m / z = 183 (M-55) ⁺ , RT = 1.879 minutes.

Step 2: Synthesis of 4-ethylpiperidine-4-carbonitrile hydrochloride

A solution of 4.0 M HCl in dioxane (10 mL) was added to a solution of tert-butyl 4-cyano-4-ethylpiperidin-1-carboxylate (3.4 g, 14.3 mmol) in DCM (10 mL). The solution was stirred at room temperature overnight. The solvent of the reaction was then removed to give the product (2.48 g, 99%) as a pale white solid.

LC-MS: m / z = 139 (M + H) ⁺ , RT = 1.076 minutes.

Example 229-2-(5- (4- (trifluoromethyl) piperidine-1-carbonyl) thiophen-2-yl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one Synthesis of (Q-609)

Step 1: Synthesis of 2-chloro-4- (4-methoxybenzyloxy) -6,7-dihydro-5H-cyclopentane [d] pyrimidine

To 100 mL of RBF was added (4-methoxyphenyl) methanol (460 mg, 3.33 mmol), 15 mL of THF and NaH (60%) (160 mg, 4.0 mmol). The mixture was stirred at room temperature for 30 minutes. Then 2,4-dichloro-6,7-dihydro-5H-cyclopentane [d] pyrimidine (600 mg, 3.19 mmol) was added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with water (20 ml) and extracted with EtOAc (100 ml). The organic layer was concentrated and purified with combiflash (isco, silica gel, UV254, 40 g, EA / PE = 1/10) to give the product. LC-MS: m / z = 291 (M + H) ⁺ , RT = 2.012 minutes.

Step 2: Synthesis of 2-chloro-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one

To 100 mL of RBF, add 2-chloro-4- (4-methoxybenzyloxy) -6,7-dihydro-5H-cyclopentane [d] pyrimidine (350 mg, 1.2 mmol), 8 mL DCM and 2 mL CF ₃ COOH. added. The mixture was stirred at room temperature for 3 hours. The reaction mixture was treated with TEA until pH = 8 and then purified with Combiflash (isco, silica gel, UV 254,40 g, EA / PE = 1/1) to give the product. LC-MS: m / z = 171 (M + H) ⁺ , RT = 1.246 minutes.

Step 3: Synthesis of 5- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) thiophen-2-carboxylic acid

2-Chloro-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one (100 mg, 0.58 mmol), 5-boronothiophene-2-carboxylic acid (350 mg,) in 100 mL of RBF. 2.03 mmol), 3 mL DME, 1.5 mL EtOH, 0.5 mL Na ₂ CO ₃ (2N) and Pd (PPh ₃ ) ₄ (100 mg, 0.086 mmol) were added. The mixture was stirred at 110 ° C. for 1 hour. The reaction mixture was then purified by combiflash (isco, silica gel, UV254, 20 g, MeOH / DCM = 1/20) to give the product. LC-MS: m / z = 263 (M + H) ⁺ , RT = 1.358 minutes.

Step 4: 2- (5- (4- (trifluoromethyl) piperidine-1-carbonyl) thiophen-2-yl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one Synthetic.

In 100 mL of RBF, 5- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) thiophen-2-carboxylic acid (80 mg, 0.30 mmol), 4- (Trifluoromethyl) piperidine hydrochloride (60 mg, 0.31 mmol), HOAT (40 mg, 0.30 mmol), HATU (80 mg, 0.34 mmol), 5 ml THF and 0.05 ml TEA were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then purified by combiflash (isco, silica gel, UV254, 20 g, MeOH / DCM = 1/20) to give the product. LC-MS (method C'): m / z = 398 (M + H) ⁺ , RT = 1.703 minutes.

Example 230-2- (3- (4- (trifluoromethyl) piperidine-1-carbonyl) phenyl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one (Q-593) ) Synthesis

Step 1: 3- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) Synthesis of benzoic acid.

In 100 mL of RBF, 2-chloro-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one (90 mg, 0.53 mmol), 3-boronobenzoic acid (200 mg, 1.20 mmol), K ₂ CO ₃ (120 mg, 0.87 mmol), 5 mL dioxane, 1 mL water and Pd (PPh ₃ ) ₄ (40 mg, 0.034 mmol) were added. The mixture was stirred at 100 ° C. for 40 hours. The reaction mixture was then purified by combiflash (isco, silica gel, UV254, 20 g, MeOH / DCM = 1/10) to give the product. LC-MS: m / z = 257 (M + H) ⁺ , RT = 0.994 minutes.

Step 2: Synthesis of 2- (3- (4- (trifluoromethyl) piperidine-1-carbonyl) phenyl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one.

In 100 mL of RBF, 3- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) benzoic acid (60 mg, 0.23 mmol), 4- (trifluoromethyl) ) Piperidine hydrochloride (50 mg, 0.26 mmol), HOAT (40 mg, 0.30 mmol), HATU (60 mg, 0.25 mmol), 3 ml THF and 0.05 ml TEA were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then purified by combiflash (isco, silica gel, UV254, 20 g, MeOH / DCM = 1/20) to give the product. LC-MS (method G'): m / z = 392 (M + H) ⁺ , RT = 1.608 minutes.

Examples 231-2-(4- (3- (3,3-difluoropyrrolidin-1-yl) azetidine-1-carbonyl) -5-methyl-1H-pyrazole-1-yl) -6,6-dimethyl- Synthesis of 6,7-dihydro-3H-cyclopentane [d] pyrimidin-4 (5H) -one (Q-1564)

Step 1: Synthesis of 3,3-dimethylhexanedioic acid.

4,4-dimethyl cyclohexanone (9 g, 71.3 mmol) and KMnO ₄ (22.5g, 142.6mmol) was dissolved in _{H 2} O in 450 mL. An aqueous solution prepared by dissolving NaOH (1 g, 25 mmol) in ₁₀ mL of H 2 O was added thereto at room temperature. The mixture was stirred at room temperature for 48 hours. Aqueous sodium bicarbonate solution was added until the purple color disappeared. The brown solid was filtered off and the filtrate was adjusted to pH = 2 with concentrated hydrochloric acid. The solution was extracted with EtOAc (150 mL x 2). The combined organics were dried and concentrated to give the product. LC-MS: m / z = 175.1 (M + H) ⁺ , RT = 0.35 minutes.

Step 2: Synthesis of dimethyl 3,3-dimethylhexanediate.

3,3-dimethyl hexane diacid (7.8 g, 44.8 mmol) in MeOH (100 mL) solution of was added concentrated _{H 2 SO 4 (1g, 10mmol} ). The mixture was stirred at 80 ° C. for 2 hours and concentrated. A _{solution of NaHCO 3} was added to the residue to give pH = 7. The mixture was extracted with EtOAc (50 mL x 2). The combined organic layers were _{dried over Na 2} SO ₄ and concentrated under vacuum to give the product. LC-MS: m / z = 203.1 (M + H) ⁺ , RT = 1.89 minutes.

Step 3: Synthesis of methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate.

A mixture of Na (230 mg, 10 mmol) solution in MeOH (8 mL) was stirred at room temperature for 5 minutes. Dimethyl 3,3-dimethylhexanediate (1 g, 5 mmol) was added. The mixture was stirred at room temperature for 30 minutes and concentrated under vacuum to remove MeOH. THF (8 mL) was added to the residue and the mixture was stirred at room temperature for 12 hours. The mixture _{was poured into H 2} O (20 mL). HCl (2N) was added up to pH = 7. The mixture was extracted with EtOAc (50 mL x 2). The organic layer was concentrated and purified on a column (silica gel, PE / EtOAc = 1/1) to give the product. LC-MS: m / z = 171.1 (M + H) +, RT = 1.77 minutes.

Step 4: Synthesis of 6,6-dimethyl-2- (methylthio) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one.

_{Methyl carbamimide thioate (594 mg, 6.6 mmol) and Na 2} CO ₃ (in a solution of methyl 4,4-dimethyl-2-oxocyclopentanecarboxylate (750 mg, 4.4 mmol) in H ₂ O (20 mL)). 1.87 g, 17.6 mmol) was added. The mixture was stirred at room temperature for 12 hours. The mixture was extracted with EtOAc (20 mL x 2). The organic layer was concentrated and purified on a column (silica gel, PE / EtOAc = 2/1) to give the product. LC-MS: m / z = 211.1 (M + H) ⁺ , RT = 1.61 minutes.

Step 5: Synthesis of 2-hydrazinyl-6,6-dimethyl-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one.

_{NH 2} NH in a solution of 6,6-dimethyl-2- (methylthio) -6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one (250 mg, 1.2 mmol) in EtOH (5 mL). ₂ H ₂ O (1 mL) was added. The mixture was stirred at 90 ° C. for 12 hours and concentrated under vacuum to give the product, which was used directly in the next step without purification. LC-MS: m / z = 195.2 (M + H) ⁺ , RT = 1.23 minutes.

Step 6: 1- (6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid Synthesis of methyl acid.

2-Hydradinyl-6,6-dimethyl-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) -one (230 mg, 1.2 mmol) in a solution of 2-((dimethyl) in EtOH (5 mL) Amino) methylene) -3-oxobutanoic acid (Z) -methyl (246 mg, 1.4 mmol) and AcOH (0.5 mL) were added. The mixture was stirred at 50 ° C. for 2 hours and concentrated under vacuum. The crude residue was purified on a column (silica gel, PE / EtOAc = 1/3) to give the product. LC-MS: m / z = 303.1 (M + H) ⁺ , RT = 1.99 minutes.

Step 7: 1- (6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid Acid synthesis.

1- (6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -5-methyl-1H-pyrazole-4-carboxylate (methyl) A solution of NaOH (60 mg, 1.5 mmol) in H ₂ O (3 mL) was added to a solution of 140 mg, 0.5 mmol) in THF (5 mL). The mixture was stirred at 35 ° C. for 3 hours and concentrated under vacuum to remove THF. Impurities were extracted by adding EtOAc (10 mL). The aqueous phase was adjusted to pH = 4 with HCl (2N). The solid was filtered to give the product. LC-MS: m / z = 289.1 (M + H) ⁺ , RT = 1.11 minutes.

Step 8: 2- (4- (3- (3,3-difluoropyrrolidin-1-yl) azetidine-1-carbonyl) -5-methyl-1H-pyrazole-1-yl) -6,6-dimethyl-6 , 7-Dihydro-3H-Cyclopentane [d] Pyrimidine-4 (5H) -on synthesis.

1- (6,6-dimethyl-4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -5-methyl-1H-pyrazole-4-carboxylic acid (49 mg) , 0.17 mmol) in THF (6 mL), NMM (68 mg, 0.68 mmol), HATU (76 mg, 0.2 mmol), HOAt (26 mg, 0.2 mmol) and 1- (azetidine-3-yl)-. 3,3-Difluoropyrrolidine (46 mg, 0.2 mmol) was added. The mixture was stirred at room temperature for 2 hours and concentrated under vacuum. The residue was purified by preparative HPLC (NH ₄ HCO ₃ ) to give the product. LC-MS (method J'): m / z = 433.2 (M + H) ⁺ , RT = 1.46 minutes.

Examples 232-2- (2-Methyl-3- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrrole-1-yl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine Synthesis of -4 (5H) -on) (Q-622)

Step 1: Synthesis of 2-methyl-1H-pyrrole-3-carboxylic acid.

To a solution of ethyl 2-methyl-1H-pyrrole-3-carboxylate (785 mg, 5.12 mmol) in dioxane (8 mL) is added a solution of _{lithium hydroxide (1.08 g, 25.62 mmol) in H 2 O (8 mL).} did. After the addition, the reaction mixture was stirred under reflux for 4 hours. The mixture was partitioned with EtOAc and HCl (1M, a.q.). The organic phase was washed with brine, dried over Na ₂ SO ₄ and concentrated to give the title compound. LC-MS: m / z = 126.2 (M + H) ⁺ , RT = 0.32 minutes.

Step 2: Synthesis of (2-methyl-1H-pyrrole-3-yl) (4- (trifluoromethyl) piperidine-1-yl) metanone.

HATU (456 mg, 1.2 mmol) in a solution of 2-methyl-1H-pyrrole-3-carboxylic acid (100 mg, 0.8 mmol) and 4- (trifluoromethyl) piperidine (147 mg, 0.96 mmol) in DMF (2 mL). ) And DIPEA (206 mg, 1.6 mmol) were added. The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated and purified by SGC (PE / EtOAc = 1/2, eluted with silica gel) to give the title compound. LC-MS: m / z = 261.1 (M + H) ⁺ , RT = 1.62 minutes.

Step 3: 2- (2-Methyl-3- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrrole-1-yl) -6,7-dihydro-3H-cyclopentane [d] pyrimidine- 4 (5H) -on synthesis.

2-Chloro-6,7-dihydro-3H-cyclopenta [d] pyrimidin-4 (5H) -one (90 mg, 0.53 mmol) and (2-methyl-1H-pyrrole-3-yl) (4- (tri) _{Cs 2} CO ₃ (344 mg, 1.06 mmol), L-proline (30 mg, 0.26 mmol) and CuI in a solution of fluoromethyl) piperidine-1-yl) metanone (164 mg, 0.63 mmol) in DMF (2 mL). (50 mg, 0.26 mmol) was added. The reaction mixture was stirred at 140 ° C. for 15 hours. The mixture was purified by pre-HPLC (high pH) to give the title compound. LC-MS (method G'): m / z = 395.0 (M + H) ⁺ , RT = 1.42 minutes.

Example 233-5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -4- (4- (trifluoromethyl) piperidine- Synthesis of 1-carbonyl) -1H-pyrazole-3-carboxamide (Q-1884)

Step 1: Synthesis of benzyl cyanoxide.

Benzyl chloroformate (5 g, 0.029 mol) and 1,4-diazabicyclo [2.2.2] octane (22 mg; 0.20 mmol) were added to the drying reaction vessel under a dry nitrogen atmosphere. Trimethylsilylnitrile (2.9 g, 0.029 mol) was added dropwise over about 1 hour. The mixture was maintained at 20 ° C. to 30 ° C. for about 3 hours until the reaction was complete. After distilling off trimethylsilyl chloride, 4.3 g of crude product was obtained, which was used directly in the next step. GC-MS: m / z = 161M ⁺ , RT = 9.249 minutes.

Step 2: Synthesis of 1-tert-butyl 4-benzyl 2-acetyl-3-aminofumalate.

Acetyl zinc (II) acetoneate (82 mg, 0.31 mmol) was added to a solution of tert-butyl 3-oxobutanoate (982 mg, 6.22 mmol) and benzyl cyanoxide (1 g, 6.21 mmol) in DCM (3 mL). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was evaporated, the residue _{was dissolved in Et 2} O (20 mL) and the suspension was filtered through Celite. The cake was _{washed with Et 2} O (15 mL) and the filtrate was evaporated. The residue was purified by silica gel chromatography (PE / EA = 12/1) to give the title compound. LC-MS: m / z = 342 (M + Na) ⁺ , RT = 1.596 minutes.

Step 3: 5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-3,4-dicarboxylic acid 4-tert -Butyl 3-benzyl synthesis.

2-Acetyl-3-aminophulate 1-tert-butyl 4-benzyl (575 mg, 1.80 mmol) in a solution of EtOH in 5 mL, 2-hydrazinyl-6,7-dihydro-3H-cyclopentane [d] pyrimidine-4 (5H) ) -On (300 mg, 1.81 mmol) was added. The suspension was heated to reflux for 15 hours. After cooling to room temperature, the suspension was filtered and the filtrate was concentrated. The residue was purified using silica gel chromatography (PE / EA = 12/1) to give the title compound. LC-MS: m / z = 395 (M-55) ⁺ , RT = 2.188 minutes.

Step 4: 3-Carbamoyl-5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclo-penta [d] pyrimidin-2-yl) -1H-pyrazole-4-carboxylic acid Synthesis of tert-butyl acid.

5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) -1H-pyrazole-3,4-dicarboxylic acid 4-tert-butyl 3 _{A MeOH solution of 8 mL of a 7M NH 3} solution in which -benzyl (440 mg, 0.98 mmol) was dissolved was placed in a sealed tube and heated at 50 ° C. for 15 hours. After cooling to room temperature, the solution was concentrated to give the title compound. LC-MS: m / z = 304 (M-55) ⁺ , RT = 1.504 minutes.

Step 5: 3-Carbamoyl-5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] -pyrimidine-2-yl) -1H-pyrazole-4-carboxylic acid Synthesis of.

3-Carbamoyl-5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta- [d] pyrimidin-2-yl) -1H-pyrazole-4-carboxylate tert-butyl To a 2 mL DCM solution (30 mg, 0.084 mmol) was added 1 mL TFA and the mixture was stirred at room temperature for 3 hours. The reaction mixture was then diluted with toluene and concentrated to give the desired product. LC-MS: m / z = 304 (M + H) ⁺ , RT = 0.407 minutes.

Step 6: 5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) -4- (4- (trifluoromethyl) piperidine-1) -Methyl) -1H-Pyrazole-3-Carboxamide synthesis.

3-Carbamoyl-5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyramidin-2-yl) -1H-pyrazol-4-carboxylic acid (26 mg, To a mixture of 2 mL of DMF of 0.084 mmol) and 4- (trifluoromethyl) piperidine hydrochloride (16 mg, 0.084 mmol), NMM (0.05 mL, 0.45 mmol), HOAt (14 mg, 0.10 mmol) and HATU (38 mg, 0.10 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours and filtered. The filtrate was purified by the prepared HPLC (NH ₄ HCO ₃ ) to give the desired product. LC-MS (method F'): m / z = 439 (M + H) ⁺ , RT = 1.356 minutes.

Example 234-6-Fluoro-2- (4- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrazole-1-yl) pyrrolo [1,2-f] [1,2,4 ] Synthesis of triazine-4 (3H) -on (Q-616)

Step 1: (1H-pyrazole-4-yl) (4- (trifluoromethyl) piperidine-1-yl) methanone

1H-Pyrazole-4-carboxylic acid (500 mg, 4.46 mmol), 4- (trifluoromethyl) piperidine hydrochloride (1.0 g, 5.29 mmol), HATU (1.2 g, 5.10 mmol) in 100 mL RBF. ), HOAT (700 mg, 5.14 mmol), 40 mL THF and 2 mL TEA were added. The mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated and purified by combiflash (isco, silica gel, UV254, 40 g, MeOH / DCM = 1/10) to give the product. LC-MS: m / z = 248 (M + H) ⁺ , RT = 1.434 minutes.

Step 2: Synthesis of 2-methyl (R) -1-tert-butyl 4,4-difluoropyrrolidine-1,2-dicarboxylic acid.

To 500 mL of RBF was added 2-methyl (R) -1-tert-butyl 4-oxopyrrolidine-1,2-dicarboxylic acid (4.0 g, 16.4 mmol) and 200 mL of DCM. The mixture was cooled to 0 ° C. and DAST (24.0 g, 150.0 mmol) in 100 ml DCM was added dropwise over 1 hour. The mixture was then stirred at room temperature for 16 hours. The reaction mixture _{was treated with NaHCO 3} (aqueous solution), extracted with DCM (300 ml) and the organic layer was concentrated to give the product. LC-MS: m / z = 166 (M-100) ⁺ , RT = 0.344 minutes.

Step 3: Synthesis of 4,4-difluoropyrrolidine-2-carboxylic acid (R) -methyl.

To 100 mL of RBF, add 2-methyl (R) -1-tert-butyl 4,4-difluoropyrrolidine-1,2-dicarboxylic acid (4.0 g, 15.1 mmol) and 40 mL HCl (4M in dioxane). did. The mixture was stirred at room temperature for 16 hours. The reaction mixture was then concentrated to give the product. LC-MS: m / z = 166 (M + H) ⁺ , RT = 0.347 minutes.

Step 4: Synthesis of 1-amino-4-fluoro-1H-pyrrole-2-carboxylate methyl.

To 250 ml of RBF, 80 ml of THF in which 4,4-difluoropyrrolidine-2-carboxylic acid (R) -methyl (2.4 g, 14.5 mmol) was dissolved was added, and 24 g of MnO ₂ was added. The mixture was stirred at 70 ° C. for 16 hours. The reaction mixture was filtered, the filtrate was concentrated and purified with combiflash (isco, silica gel, UV254, 40 g, EA / PE = 1/3) to give the product. LC-MS: m / z = 144 (M + H) ⁺ , RT = 1.528 minutes.

Step 5: Synthesis of 1-amino-4-fluoro-1H-pyrrole-2-carboxylate methyl.

To 500 mL of RBF, _{200 mL of Et 2} O solution in which _{NH 4} Cl (6.0 g, 112 mmol) was dissolved was added. The mixture was cooled to −5 ° C. and 9.4 ml of NH ₄ OH was added dropwise with vigorous stirring. Then 145 ml of NaClO was added dropwise over 2 hours. The mixture was stirred for 15 minutes and the layers were separated. The organic layer was washed with brine, dried with CaCl ₂ , and used in the next step without further purification. Then, to 100 ml of RBF, methyl 4-fluoro-1H-pyrrole-2-carboxylate (1.7 g, 11.8 mmol) and 30 ml of DMF were added. The mixture was cooled to 0 ° C. and NaH (60%) (600 mg, 15.0 mmol) was added. After 45 minutes, pre-prepared NH ₂ Cl (100 ml) was added dropwise. The mixture was stirred at room temperature for 2 hours. The reaction mixture was extracted with EtOAc (200 ml), the organic layer was concentrated and purified with Combiflash (isco, silica gel, UV254, 40 g, EA / PE = 1/5) to give the product. LC-MS: m / z = 159 (M + H) ⁺ , RT = 1.49 minutes.

Step 6: Synthesis of 1- (3-benzoylthioureide) -4-fluoro-1H-pyrrole-2-carboxylate methyl.

To 250 mL of RBF, methyl 1-amino-4-fluoro-1H-pyrrole-2-carboxylate (1.7 g, 10.76 mmol), THF 80 mL and benzoyl isothiocyanate (1.8 g, 11.04 mmol) were added. The mixture was stirred at room temperature _{under N 2} for 16 hours. The reaction mixture was concentrated and purified by combiflash (isco, silica gel, UV254, 40 g, EA / PE = 1/4) to give the product. LC-MS: m / z = 322 (M + H) ⁺ , RT = 1.823 minutes.

Step 7: Synthesis of 6-fluoro-2-mercaptopyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one.

To 100 mL of RBF was added 1- (3-benzoylthioureide) -4-fluoro-1H-pyrrole-2-carboxylate methyl (1.5 g, 4.67 mmol) and 10 mL NaOH (2N). The mixture was stirred at 85 ° C. _{under N 2} for 1.5 hours. The reaction mixture was cooled to 0 ° C., EtOH (5 ml) and HOAc (2 ml) were added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered and _{washed with Et 2} O (20 ml) to give the product. LC-MS: m / z = 186 (M + H) ⁺ , RT = 0.67 minutes.

Step 8: Synthesis of 6-fluoro-2- (methylthio) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one.

To 100 mL of RBF, 6-fluoro-2-mercaptopyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one (700 mg, 3.78 mmol) and 20 ml of THF were added, and MeI ( 700 mg (4.92 mmol) was added. The mixture was stirred at 45 ° C. _{under N 2} for 1 hour. The reaction mixture _{was treated with NaHCO 3} (aqueous solution) and filtered to give the product. LC-MS: m / z = 200 (M + H) ⁺ , RT = 1.551 minutes.

Step 9: Synthesis of 6-fluoro-2- (methylsulfonyl) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one.

To 50 mL of RBF, 6-fluoro-2- (methylthio) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one (100 mg, 0.50 mmol) and 4 ml of HOAc were added. And added to ₂ ml of H ₂ O 2. The mixture was stirred at 170 ° C. with microwaves for 15 hours. The reaction mixture was filtered to give the product. LC-MS: m / z = 232 (M + H) ⁺ , RT = 1.368 minutes.

Step 10: 6-Fluoro-2- (4- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrazol-1-yl) pyrrolo [1,2-f] [1,2,4] Synthesis of triazine-4 (3H) -on.

In a microwave tube, 6-fluoro-2- (methylsulfonyl) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one (100 mg, 0.43 mmol), (1H-pyrazole). -4-yl) (4- (trifluoromethyl) piperidine-1-yl) metanone (110 mg, 0.44 mmol), CS ₂ CO ₃ (160 mg, 0.49 mmol) and 2 ml NMP were added. The mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated and purified by combiflash (isco, silica gel, UV254, 20 g, MeOH / DCM = 1/10) to give the product. LC-MS (method G'): m / z = 399 (M + H) ⁺ , RT = 1.399 minutes.

Example 235-236

Examples 235-236 of Table 26 (Table 17) were prepared in a manner similar to Example 234, starting from the corresponding starting material.

Example 237-7-Fluoro-2- (4- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrazole-1-yl) pyrrolo [1,2-f] [1,2,4 ] Synthesis of triazine-4 (3H) -on (Q-525).

Step 1: Synthesis of 2,4-dichloro-7-fluoropyrrolo [1,2-f] [1,2,4] triazine.

2,4-Dichloropyrrolo [1,2-f] [1,2,4] triazine (6.0 g, 31.9 mmol) and 1- (chloromethyl) -4-fluoro-1,4-diazonia-bicyclo [ 2.2.2] octane tetrafluoroborate (22.6 g, 63.8 mmol) the mixture of acetonitrile (250 mL) of, _{N 2} atmosphere and stirred for 16 hours at 45 ° C.. The mixture was concentrated and the residue was diluted with DCM (400 _mL), washed with H 2 O (50mL × 3) , were dried over _Na 2 SO _4. The filtrate was concentrated to give a crude product. LC-MS: m / z = 206.0 (M + H) ⁺ , RT = 1.873 minutes.

Step 2: Synthesis of 2-chloro-7-fluoropyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one.

In a mixture of 2,4-dichloro-7-fluoropyrrolo [1,2-f] [1,2,4] triazine (6.33 g, 30.7 mmol) in THF / H ₂ O (30 ml / 30 mL). Sodium hydroxide (6.16 g, 154 mmol) was added. The mixture was stirred at 50 ° C. for 4 hours and cooled to room temperature. The mixture was adjusted to pH = 3-4 with 4N HCl and extracted with EtOAc (100 mL × 4). The combined organics were _{dried over Na 2} SO ₄ and concentrated to give 5.2 g of crude product. 2 g of crude product was purified by preparative HPLC (TFA / CH ₃ CN / H ₂ O) to give the product. LC-MS: m / z = 188.0 (M + H) ⁺ , RT = 1.486 minutes.

Step 3: 7-Fluoro-2- (4- (4- (trifluoromethyl) piperidine-1-carbonyl) -1H-pyrazol-1-yl) pyrrolo [1,2-f] [1,2,4] Synthesis of triazine-4 (3H) -on.

2-Chloro-7-fluoropyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one (302 mg, 1.61 mmol), (1H-pyrazol-4-yl) (4-) A mixture of (trifluoromethyl) piperidine-1-yl) methanone (398 mg, 1.61 mmol) and Cs ₂ CO ₃ (1049 mg, 3.22 mmol) in a dry DMF (20 mL) solution with L-proline (93 mg, 0. 8 mmol) and CuI (152mg, 0.8mmol) was added under _{N 2} atmosphere. The mixture was stirred at 140 ° C. for 20 hours. The mixture was cooled to room _temperature, diluted with H 2 O (100mL), the pH was adjusted to 3-4 with 1N HCl, and extracted with EtOAc (100mL × 5). The combined organics were _{dried over Na 2} SO ₄ and concentrated. The residue was purified by preparative HPLC (TFA / CH ₃ CN / H ₂ O) to give a crude product, which was further purified by _{preparative HPLC (NH 4} / HCO ₃ / CH ₃ CN / H _{2 O).} The product was obtained. LC-MS (method D'): m / z = 399.2 (M + H) ⁺ , RT = 1.002 minutes.

Example 238-239

Examples 238-239 of Table 27 (Table 18) were prepared in the same manner as in Example 237, starting with the corresponding starting material.

Examples 240-2- (5-methyl-4- (4- (4- (trifluoromethoxy) phenylsulfonyl) piperazine-1-carbonyl) -1H-pyrazole-1-yl) pyrrolo [1,2-f] [1,2,4] Synthesis of triazine-4 (3H) -on (Q-1798)

Step 1: tert-Butyl-4- (5-methyl-1- (4-oxo-3,4-dihydropyrolo [1,2-f] [1,2,4] triazine-2-yl) -1H- Synthesis of pyrazole-4-carbonyl) piperazin-1-carboxylic acid.

5-Methyl-1- (4-oxo-3,4-dihydropyrrolo [1,2-f] [1,2,4] triazine-2-yl) -1H-pyrazole-4-carboxylic acid (2 g, 7) .715 mmol) and tert-butyl-piperazine-1-carboxylic acid (1.6 g, 8.487 mmol) in THF (40 mL) solution with HATU (3.52 g, 9.258 mmol), HOAT (1.05 g, 7.48 mmol). 715 mmol) and TEA (2.34 g, 23.146 mmol) were added and the reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated and purified by SGC (eluted with DCM / MeOH = 20/1) to give the title compound. LC-MS: m / z = 428.3 (M + H) ⁺ , RT = 1.535 minutes.

Step 2: 2- (5-Methyl-4- (piperazin-1-carbonyl) -1H-pyrazol-1-yl) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H)- Synthesis of on-dihydrochloride.

tert-Butyl-4- (5-methyl-1- (4-oxo-3,4-dihydropyrrolo [1,2-f] [1,2,4] triazine-2-yl) -1H-pyrazole-4 Hydrochloric acid (20 mL, 4 M in dioxane) was added to a solution of −carbonyl) piperazine-1-carboxylic acid (3.88 g, 9.077 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated to give the title compound. LC-MS: m / z = 328.2 (M + H) ⁺ , RT = 1.146 minutes.

Step 3: 2- (5-Methyl-4- (4- (4- (trifluoromethoxy) phenylsulfonyl) piperazine-1-carbonyl) -1H-pyrazole-1-yl) pyrrolo [1,2-f] [ 1,2,4] Synthesis of triazine-4 (3H) -one.

2- (5-Methyl-4- (piperazin-1-carbonyl) -1H-pyrazole-1-yl) pyrrolo [1,2-f] [1,2,4] triazine-4 (3H) -one dihydrochloride To a solution of salt (50 mg, 0.125 mmol) and TEA (51 mg, 0.50 mmol) in DCM (3 mL) was added 4- (trifluoromethoxy) benzene-1-sulfonyl chloride (39 mg, 0.15 mmol). The reaction mixture was stirred at room temperature for 15 hours. The mixture was purified by preparative HPLC (high pH) to give the title compound. LC-MS (method J'): m / z = 552.2 (M + H) ⁺ , RT = 1.671 minutes.

Example 241-289

Examples 241-289 of Table 28 (Table 19) were prepared in the same manner as in Example 240, starting with the corresponding starting material.

Example 290-2-(5-methyl-4- (2,6-diazaspiro [4.5] decane-2-carbonyl) -1H-pyrazole-1-yl) -6,7-dihydro-3H-cyclopentane [ d] Synthesis of pyrimidine-4 (5H) -on (Q-577).

Step 1: 2- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) -2 , 6-Diazaspiro [4.5] Synthesis of tert-butyl decane-6-carboxylic acid.

5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) -1H-pyrazole-4-carboxylic acid (50 mg, 0.19 mmol), Tert-butyl 2,6-diazaspiro [4.5] decane-6-carboxylic acid (55 mg, 0.19 mmol), HATU (109.6 mg, 0.29 mmol), HOAt (39 mg, 0.29 mmol) and TEA (0) 0.05 mL, 0.38 mmol) was stirred at room temperature for 2 hours. The reaction was concentrated. The residue was purified by preparative TLC (DCM / MeOH = 15/1, silica, UV254) to give the title compound. LC-MS: m / z = 483 (M + H) ⁺ , RT = 1.544 minutes.

Step 2: 2- (5-Methyl-4- (2,6-diazaspiro [4.5] decane-2-carbonyl) -1H-pyrazole-1-yl) -6,7-dihydro-3H-cyclopentane [d] ] Synthesis of pyrimidine-4 (5H) -one.

2- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) -2,6 Hydrochloric acid (4M in dioxane, 1 mL) was added to a solution of tert-butyl (50 mg, 0.1 mmol) of −diazaspiro [4.5] decane-6-carboxylic acid in DCM (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction was concentrated. The residue was purified by preparative HPLC (high pH) to give the title compound. LC-MS (method C'): m / z = 383 (M + H) ⁺ , RT = 1.21 minutes.

Examples 291-292

Examples 291-292 of Table 29 (Table 20) were prepared in a manner similar to Example 290, starting from the corresponding starting material.

Examples 293-3- (4- (5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazol-4-) Synthesis of (carbonyl) piperazine-1-carbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (Q-627)
Examples 293-3- (4- (5-methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazol-4-) Synthesis of (carbonyl) piperazine-1-carbonyl) bicyclo [1.1.1] pentane-1-carbonitrile (Q-632)

Step 1: Synthesis of bicyclo [1.1.1] pentane-1,3-dicarboxylic acid dimethyl.

_{SOCl 2} (6 mL) was added dropwise to a solution of bicyclo [1.1.1] pentane-1,3-dicarboxylic acid (1 g, 6.4 mmol) in MeOH (50 mL). The reaction was stirred at 80 ° C. for 15 hours. The reaction was concentrated. The residue was washed with ₃ aqueous NaHCO solution (80 mL) and extracted with DCM (2 x 60 mL). The combined organic layers were concentrated to give the title compound.

Step 2: Synthesis of 3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid.

NaOH (2M, 3 mL) was added to a solution of dimethyl bicyclo [1.1.1] pentane-1,3-dicarboxylic acid (1.1 g, 5.98 mmol) in THF / MeOH (1/1, 10 mL). The reaction was stirred at room temperature for 15 hours. The reaction was concentrated. The residue was treated with water (50 mL), adjusted to pH = 5 with HCl (2M) and extracted with DCM (2 x 50 mL). The combined organic layers were concentrated to give the title compound.

Step 3: Synthesis of piperazine-1-carboxylic acid 4- (3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carbonyl) tert-butyl.

3- (Methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (600 mg, 3.53 mmol), piperazine-1-carboxylic acid tert-butyl (656 mg, 3.53 mmol), EDCI (1.01 g) A mixture of 5,29 mmol), HOBt (715 mg, 5.29 mmol) and TEA (1 mL, 7.06 mmol) in THF (30 mL) was stirred at room temperature for 15 hours. The reaction was treated with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layers were concentrated to give the title compound. LC-MS: m / z = 283 (M-56 + H) ⁺ ; RT = 1.68 minutes.

Step 4: Synthesis of 3- (piperazine-1-carbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid methyl hydrochloride.

4- (3- (Methoxycarbonyl) bicyclo [1.1.1] pentane-1-carbonyl) piperazine-1-carboxylic acid tert-butyl (1.05 g, 3.1 mmol) in DCM (10 mL) solution with HCl (4M in dioxane, 10mL) was added. The mixture was stirred at room temperature for 2 hours. The reaction was concentrated to give the title compound (850 mg, 99%). LC-MS: m / z = 239 (M + H) +, RT = 0.92 minutes.

Step 5: 3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) ) Piperazine-1-carbonyl) Bicyclo [1.1.1] Synthesis of methyl pentane-1-carboxylate.

5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopenta [d] pyrimidin-2-yl) -1H-pyrazole-4-carboxylic acid (585 mg, 2.25 mmol), 3- (Piperazine-1-carbonyl) bicyclo [1.1.1] Pentan-1-carboxylate methyl hydrochloride (850 mg, 3.1 mmol), HATU (1.28 g, 3.37 mmol), THF (460 mg, 3) A mixture of a solution of .37 mmol) and TEA (1 mL) in THF (30 mL) was stirred at room temperature for 15 hours. The reaction was concentrated. The residue was purified by combiflash (40 g, DCM / MeOH = 20/1, silica, UV254) to give the title compound. LC-MS: m / z = 481 (M + H) ⁺ , RT = 1.48 minutes.

Step 6: 3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) ) Piperazine-1-carbonyl) Bicyclo [1.1.1] Synthesis of pentane-1-carboxylic acid.

3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) piperazine- LiOH (2M, 1 mL) was added to a solution of methyl 1-carbonyl) bicyclo [1.1.1] pentan-1-carboxylate (120 mg, 0.25 mmol) in THF / MeOH (1/1, 4 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction was treated with water (20 mL) and adjusted to pH = 5 with HCl (2M). The mixture was extracted with EtOAc (2 x 30 mL). The combined organic layers were concentrated. The residue was purified by preparative HPLC (low pH) to give the title compound. LC-MS (method C'): m / z = 467 (M + H) ⁺ , RT = 1.34 minutes.

Step 7: 3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) ) Synthesis of piperazine-1-carbonyl) bicyclo [1.1.1] pentane-1-carboxamide.

3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) piperazine- 1-carbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid (80 mg, 0.17 mmol), NH ₄ Cl (13.6 mg, 0.26 mmol), THF (49.2 mg, 0.26 mmol), A mixture of EDCI (34.7 mg, 0.26 mmol) and TEA (0.07 mL) in THF (5 mL) was stirred at room temperature for 15 hours. The reaction was concentrated. The residue was purified by preparative HPLC (low pH) to give the title compound. LC-MS: m / z = 466 (M + H) ⁺ , RT = 1.28 minutes.

Step 8: 3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) ) Synthesis of piperazine-1-carbonyl) bicyclo [1.1.1] pentane-1-carbonitrile.

3- (4- (5-Methyl-1- (4-oxo-4,5,6,7-tetrahydro-3H-cyclopentane [d] pyrimidin-2-yl) -1H-pyrazole-4-carbonyl) piperazine- TEA (0.6 mL) and trifluoroacetic anhydride (0.4 mL) in a solution of 1-carbonyl) bicyclo [1.1.1] pentane-1-carboxamide (45 mg, 0.1 mmol) in DCM (3 mL). Was added. The mixture was stirred at room temperature for 15 hours. The reaction was concentrated. The residue was purified by preparative HPLC (high pH) to give the title compound. LC-MS (method F'): m / z = 448 (M + H) ⁺ , RT = 1.35 minutes.

Example 295-2- (4- (2,2-dimethyl-4- (2,2,2-trifluoroethyl) piperazine-1-carbonyl) -5-methyl-1H-pyrazole-1-yl) pyrrolo [ 1,2-f] [1,2,4] Synthesis of triazine-4 (3H) -on (Q-949)

Step 1: 5-Methyl-1-chloride (4-oxo-3,4-dihydropyrrolo [1,2-f] [1,2,4] triazine-2-yl) -1H-pyrazole-4-carbonyl Preparation.

5-Methyl-1- (4-oxo-3,4-dihydropyrrolo [1,2-f] [1,2,4] triazine-2-yl) -1H-pyrazole-4-carboxylic acid (50 mg, 0) DMF (3 drops) was added to a solution of .193 mmol) and oxalyl dichloride (74 mg, 0.579 mmol) in DCM (8 mL) at room temperature. The mixture was stirred at room temperature for 2 hours until the reaction was complete. The mixture was concentrated to give the crude product (80 mg), which was used directly in the next step.

Step 2: 2- (4- (2,2-dimethyl-4- (2,2,2-trifluoroethyl) piperazine-1-carbonyl) -5-methyl-1H-pyrazole-1-yl) pyrrolo [1 , 2-f] [1,2,4] Preparation of triazine-4 (3H) -one.

5-Methyl-1- (4-oxo-3,4-dihydropyrrolo [1,2-f] [1,2,4] triazine-2-yl) -1H-pyrazole-4-carbonyl (80 mg, 0) .288 mmol), 3,3-dimethyl-1- (2,2,2-trifluoroethyl) piperazine hydrochloride (74 mg, 0.317 mmol) and TEA (87 mg, 0.864 mmol) in DCM (8 mL). Stir overnight at room temperature. The mixture was concentrated to remove solvent and the residue was purified by preparative HPLC (high pH) to give the title compound. LC-MS (method F'): m / z = 438.1 (M + H) ⁺ , RT = 1.67 minutes.

Example 296-299

Examples 296-299 of Table 30 (Table 21) were prepared in a manner similar to Example 295, starting from the corresponding starting material.

Examples 300-946

Examples 300-946 of Table 31 (Table 22) were prepared according to the methods described herein starting with the appropriate starting material.

Preparation Example 9 Amine formation

Preparation of 4- (azetidine-3-yl) -2-fluoropyridine TFA salt:

Step 1: (1- (tert-butoxycarbonyl) azetidine-3-yl) zinc (II) iodide.

1,2-dibromoethane (1.992g, 10.6mmol) and, _{N 2} atmosphere, was added to a suspension of Zn in dry THF (40mL) (2.86g, 44.1mmol ). The mixture was refluxed for 15 minutes and cooled to room temperature. TMSC1 (764 mg, 7.08 mmol) was added slowly to the mixture. After the addition, the mixture was stirred at room temperature for 45 minutes, then dried THF (10 mL) of tert-butyl 3-iodoazetidine-1-carboxylate (5 g, 17.7 mmol) was added. The mixture was stirred at 40 ° C. for 2 hours to give a zinc reagent solution, which was used directly in the next step.

Step 2: Synthesis of tert-butyl 3- (2-fluoropyridin-4-yl) azetidine-1-carboxylate.

A solution of 4-bromo-2-fluoropyridine (3 g, 17.142 mmol) in THF (10 ml) was added to Pd (dba) ₃ (1.57 g, 1.714 mmol) and Pd (2-furyl) ₃ (1.2 g,). to a mixture of 5.143mmol), it was added under _{N 2} atmosphere. Then a solution of (1- (tert-butoxycarbonyl) azetidine-3-yl) zinc (II) iodide (7.2 g, 20.571 mmol) in THF (50 mL) was added. The mixture was stirred at 60 ° C. for 5 hours. The reaction was _{quenched with H 2} O (10 mL). The precipitate was filtered. The filtrate was extracted with EtOAc (30 mL x 2) and washed with water (200 mL). The combined organic matter was dried _{over Na 2} SO _4. The solvent was then removed and the residue was _{purified by silica gel chromatography using CH 2} Cl ₂ / MeOH: 50/1 to give the product. LC-MS: m / z = 253 (M + H) ⁺ , RT = 1.457 minutes.

Step 3: Synthesis of 4- (azetidine-3-yl) -2-fluoropyridine TFA salt.

TFA (5 mL) was added to a solution of tert-butyl 3- (2-fluoropyridin-4-yl) azetidine-1-carboxylic acid (1.926 g, 7.634 mmol) in DCM (5 mL). The solution was stirred at room temperature for 3 hours. The solvent was removed from the reaction to give the product, which was used in the next step without further purification. LC-MS: m / z = 153 (M + H) ⁺ .

Preparation of 1- (3,3-difluorocyclobutyl) piperazine:

Step 1: Synthesis of 1-benzyl-4- (3,3-difluorocyclobutyl) piperazine

N-Benzyl-2-chloro-N- (2-chloroethyl) ethaneamine hydrochloride (2.3 g, 8.61 mmol), 3,3-difluorocyclobutaneamine hydrochloride (1.0 g, 6.99 mmol) in 100 mL of RBF. ), 20 mL EtOH, and 6 mL DIPEA were added. The mixture was stirred under reflux and under N ₂ for 16 hours. The reaction mixture was concentrated and purified by combiflash (isco, silica gel, UV254, 40 g, EA / PE = 1/3) to give the product. LC-MS (UV214) 267.2 (M + H) ⁺ , RT = 2.01 minutes.

Step 2: Synthesis of 1- (3,3-difluorocyclobutyl) piperazine.

To 100 mL of RBF, 1-benzyl-4- (3,3-difluorocyclobutyl) piperazine (1.0 g, 3.76 mmol), 30 mL EtOAc, 0.05 mL HOAc, and 400 mg Pd (OH) ₂ . added. The mixture was stirred at room temperature under H ₂ (2 atm) for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to give the title product. LC-MS (UV214) 177.2 (M + H) ⁺ , RT = 1.17 minutes.

Preparation of 1- (2,2-difluorocyclobutyl) piperazine hydrochloride:

Step 1: Synthesis of tert-butyl-4- (2-oxocyclobutyl) piperazine-1-carboxylic acid

A solution of 1,2-bis (trimethylsilyloxy) cyclobuta-1-ene (12.5 g, 54.24 mmol) in MeOH (40 mL) with tert-butyl-piperazine-1-carboxylic acid (10.1 g, 54.24 mmol). A solution of MeOH (60 mL) was added dropwise over 30 minutes. After the addition, the reaction mixture was stirred at room temperature for 15 hours. The mixture was concentrated and purified by SGC (eluted with DCM / MeOH = 20/1) to give the title compound. LC-MS: m / z = 199.1 (M-56) ⁺ , RT = 1.80 minutes.

Step 2: Synthesis of tert-butyl-4- (2,2-difluorocyclobutyl) piperazine-1-carboxylic acid.

DAST (13.69 g, 84.93 mmol) was added to a solution of tert-butyl-4- (2-oxocyclobutyl) piperazine-1-carboxylic acid (7.2 g, 28.31 mmol) in DCM (50 mL). The reaction mixture was stirred at room temperature for 15 hours. This was then _{quenched with saturated NaHCO 3} (100 mL), extracted with DCM (80 mL × 3), and the combined organics were _{dried over Na 2} SO ₄ and concentrated. The residue was purified by SGC (eluted with PE / EtOAc = 10/1 to 1/1) to give the title compound. LC-MS: m / z = 277.2 (M + H) ⁺ , RT = 2.01 minutes.

Step 3: Synthesis of 1- (2,2-difluorocyclobutyl) piperadi hydrochloride.

HCl (4 mL, 4 M in dioxane) was added to a solution of tert-butyl-4- (2,2-difluorocyclobutyl) piperazine-1-carboxylic acid (950 mg, 3.44 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 15 hours, concentrated and washed with EtOAc (40 mL) to give the title compound. LC-MS: m / z = 177.2 (M + H) ⁺ , RT = 1.15 minutes.

Preparation of 2- (Piperidin-4-yl) Oxazole-4-Carbonitrile Hydrochloride:

Step 1: Synthesis of methyl 2- (1- (tert-butoxycarbonyl) piperidine-4-yl) -2,5-dihydrooxazole-4-carboxylate.

A mixture of 2 liters of DCM in which methyl 2-amino-3-hydroxypropanoate (80 g, 516.4 mmol) and DABCO (157.74 g, 1408.45 mmol) were dissolved was stirred for 40 minutes. Then tert-butyl 4-formylpiperidine-1-carboxylate (100 g, 469.48 mmol) was added to the mixture and stirred at room temperature for 40 minutes. The mixture was cooled to 0 ° C. and then 500 mL of a DCM solution in which NBS (68.68 g, 516.4 mmol) was dissolved was added dropwise to the mixture. The mixture was warmed to room temperature and stirred overnight. The reaction was quenched with saturated _{aqueous Na 2} S ₂ O ₅ , extracted with DCM (300 ml x 2) and washed with _{saturated aqueous NaHCO 3.} The combined organics were _{dried over Na 2} SO ₄ , concentrated and purified by SGC (PE / EA = 3/2) to give the title compound. LC-MS: m / z = 335 (M + 23) ⁺ , RT = 1.97 minutes.

Step 2: Synthesis of methyl 2- (1- (tert-butoxycarbonyl) piperidine-4-yl) oxazole-4-carboxylate.

Methyl 2- (1- (tert-butoxycarbonyl) piperidine-4-yl) -2,5-dihydrooxazole (10 g, 32.25 mmol), NBS (5.74 g, 32.25 mmol) and K ₂ CO ₃ (5) A mixture of 100 mL of DCE solution in which .34 g (38.7 mmol) was dissolved was heated to 80 ° C. and stirred for 2 hours. The mixture was then cooled to 0 ° C., quenched with saturated _{aqueous Na 2} S ₂ O ₅ solution, extracted with DCM (100 ml × 3) and further washed with aqueous _{saturated Na HCO 3 solution.} The combined organics were _{dried over Na 2} SO ₄ , concentrated and further purified by SGC (PE / EA = 3/2) to give the title compound. LC-MS: m / z = 333 (M + 23) ⁺ , RT = 1.48 minutes.

Step 3: Synthesis of 2- (1- (tert-butoxycarbonyl) piperidine-4-yl) oxazole-4-carboxylic acid.

THF / H of oxazole-4-carboxylic acid 2- (1- (tert-butoxycarbonyl) piperidine-4-yl) methyl (6 g, 19.35 mmol) and LiOH · H _{2 O (2.438 g, 58.06 mmol) The 2} O (40 mL, v / v = 1/1) solution was stirred at 25 ° C. for 16 hours. The mixture was adjusted to pH = 3 with 1N HCl and then extracted with EA (60 mL × 3). The combined organic matter was dried _{over Na 2} SO _4. The solvent was removed under reduced pressure. The residue was used directly in the next step. LC-MS: m / z = 319 (M + 23) ⁺ , RT = 1.34 minutes.

Step 4: Synthesis of 4- (4-carbamoyloxazole-2-yl) piperidine-1-carboxylic acid tert-butyl.

2- (1- (tert-butoxycarbonyl) piperidine-4-yl) oxazole-4-carboxylic acid (4 g, 13.51 mmol), NH ₄ Cl (1.702 g, 27.02 mmol), HATU (6.16 g, A mixture of 50 mL of a THF solution in which 16.212 mmol), HOAt (2.204 g, 16.212 mmol) and TEA (4.093 g, 40.53 mmol) were dissolved was stirred at room temperature overnight. The reaction was quenched with water, extracted with EA (60 mL x 3) and washed with aqueous NaCl solution. The combined organics were _{dried over Na 2} SO ₄ , concentrated and purified with SGC (PE / EA = 1/4) to give the title compound. LC-MS: m / z = 318 (M + 23) ⁺ , RT = 1.77 minutes.

Step 5: Synthesis of piperidine-1-carboxylic acid 4- (4-cyanooxazole-2-yl) tert-butyl.

Piperidine-1-carboxylic acid 4- (4-carbamoyloxazole-2-yl) tert-butyl (2.5 g, 8.474 mmol) in TEA (10 mL) and THF (10 mL) solution with THFA (4 mL) at 0 ° C. Was added by dropping. The reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by SGC (PE / EA = 2/1) to give the title compound. LC-MS: m / z = 300 (M + 23) ⁺ ; RT = 2.01 minutes.

Step 6: 2- (Piperidin-4-yl) Oxazole-4-Carbonitrile Hydrochloride.

3N HCl / EA (5 mL) was added to a solution of tert-butyl 4- (4-cyanooxazol-2-yl) piperidine-1-carboxylate (1.3 g, 4.693 mmol) in EA (5 mL). The mixture was stirred at room temperature for 1 hour. The resulting precipitate was collected, washed with diethyl ether and then dried under vacuum to give the title compound. LC-MS: m / z = 178 (M + 1) ⁺ , RT = 0.21 minutes.

Preparation of 5- (azetidine-2-yl) -2-fluoropyridine hydrochloride:

Step 1: Synthesis of (E) -N-((6-fluoropyridin-3-yl) methylene) -2-methylpropan-2-sulfinamide.

A mixed solution of 6-fluoronicotine aldehyde (4.7 g, 37.6 mmol) and titanium isopropoxide (1.37 g, 75.2 mmol) in dry THF (90 mL) was stirred under nitrogen for 30 minutes. Then a solution of 2-methyl-2-propanesulfinamide (4.56 g, 37.6 mmol) in dry THF (10 mL) was added. The reaction mixture was stirred at room temperature for 16 hours, diluted with EtOAc (200 mL) and MeOH (50 mL), then brine (100 mL) was added slowly. The mixture was stirred at room temperature for 30 minutes and filtered. The solid was washed with EtOAc (200 mL x 2). The filtrate was extracted with EtOAc (200 mL x 3). The combined organics were washed with brine (50 mL x 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified with SGC (PE / EtOAc = 5/1) to give the title compound. LC-MS: m / z = 303 (M + H) ⁺ , RT = 1.61 minutes.

Step 2: Synthesis of 3- (1,1-dimethylethylsulfinamide) -3- (6-fluoropyridin-3-yl) methyl propanoate.

1,2-Dibromoethane (7.53 g, 40.1 mmol) was added to a suspension of dried THF (130 mL) of zinc powder (13.13 g, 200.7 mmol). The mixture was stirred under reflux for 20 minutes and then cooled to room temperature. TMSCl (2.91 g, 26.8 mmol) was added, and the mixture was stirred at room temperature for 1 hour. Then, methyl 2-bromoacetate (10.05 g, 66.9 mmol) was added, and the mixture was stirred at 50 ° C. for 2 hours. The mixture was cooled to room temperature. The resulting solution is a dry THF (20 mL) solution of (E) -N-((6-fluoropyridin-3-yl) methylene) -2-methylpropan-2-sulfinamide (5.09 g, 22.3 mmol). Was added dropwise at 0 ° C. The mixture was stirred at 0 ° C. for 6 hours, diluted with DCM (100 mL), washed with 0.25 M aqueous citric acid solution (200 mL x 2), saturated _{aqueous NaHCO 3} solution (50 mL x 2), brine (50 mL x 2). It _{was dried over Na 2} SO ₄ and concentrated to give the title compound. LC-MS: m / z = 303 (M + H) ⁺ , RT = 1.61 minutes.

Step 3: Synthesis of N- (1- (6-fluoropyridin-3-yl) -3-hydroxypropyl) -2-methylpropan-2-sulfinamide.

_{1M LiAlH 4} THF in a dry THF (50 mL) solution of methyl 3- (1,1-dimethylethylsulfinamide) -3- (6-fluoropyridin-3-yl) methyl propanoate (3.32 g, 11.0 mmol). The solution (22 mL, 22 mol) was added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes, diluted with EtOAc (200 mL) and quenched in small portions with _{Na 2} SO _{4 / 10H 2} O (22 g). The mixture was stirred at room temperature for 30 minutes and filtered. The solid was washed with MeOH (20 mL). The filtrate was _{dried over Na 2} SO ₄ and concentrated to give the crude title compound. LC-MS: m / z = 275 (M + H) ⁺ . RT = 1.60 minutes.

Step 4: Synthesis of 5- (1- (tert-butylsulfinyl) azetidine-2-yl) -2-fluoropyridine.

Water in a dry THF (50 mL) solution of N- (1- (6-fluoropyridin-3-yl) -3-hydroxypropyl) -2-methylpropan-2-sulfinamide (2.7 g, 9.85 mmol). Potassium oxide (1.65 g, 29.55 mmol) and 4-methylbenzene-1-sulfonyl chloride (2.25 g, 11.82 mmol) were added. The mixture was stirred under reflux for 5 hours and cooled to room temperature. The mixture was diluted with DCM (200 mL), washed with brine (20 mL x 2), dried over Na ₂ SO ₄ and concentrated. The residue was purified with SGC (PE / EtOAc = 2/1) to give the title compound. LC-MS: m / z = 257 (M + H) ⁺ ; RT = 1.61 minutes.

Step 5: Synthesis of 5- (azetidine-2-yl) -2-fluoropyridine hydrochloride.

4-M HCl / dioxane solution (16.7 mL, 66) in DCM (20 mL) solution of 5- (1- (tert-butylsulfinyl) azetidine-2-yl) -2-fluoropyridine (1.14 g, 4.45 mmol) 0.8 mmol) was added at 0 ° C. The mixture was stirred at room temperature for 30 minutes and then concentrated to give the title compound. LC-MS: m / z = 124 (M-28) ⁺ , RT = 0.308 minutes.

Preparation of 6-cyclopropyl-3,6-diazabicyclo [3.1.1] heptane dihydrochloride:

Step 1: Synthesis of tert-butyl 6-cyclopropyl-3,6-diazabicyclo [3.1.1] heptane-3-carboxylate.

3,6-Diaza-bicyclo [3.1.1] tert-butyl (1.5 g, 7.58 mmol) heptane-3-carboxylate and (1-ethoxycyclopropoxy) trimethylsilane (3.1 ml, 15.45 mmol) ) Was dissolved in 10 ml of MeOH solution and 10 ml of THF solution, and sodium cyanoborohydride (715 mg, 11.35 mmol) and acetic acid (2.2 ml, 38.50 mmol) were added. The mixture was stirred at 60 ° C. _{under N 2} for 12 hours. After cooling to room temperature, 1 ml of water was added and the mixture was stirred for 5 minutes. It was then treated with 1N NaOH (2.5 ml) and stirred for 15 minutes. The mixture was concentrated and the aqueous phase was extracted with DCM (100 ml). The organic phase was washed with 1N NaOH (50 ml). The combined aqueous phase was extracted with DCM (2 x 100 ml). The combined organics were washed with brine, dried over sodium sulphate and concentrated to give the crude product, which was used in the next step without further purification. LC-MS: m / z = 239 (M + H) ⁺ , RT = 2.26 minutes.

Step 2: Synthesis of 6-cyclopropyl-3,6-diaza-bicyclo [3.1.1] heptane dihydrochloride.

25 mL of 4N HCl in 40 mL of dichloromethane solution of tert-butyl 6-cyclopropyl-3,6-diaza-bicyclo [3.1.1] heptane-3-carboxylic acid (1.8 g crude, 7.56 mmol). 1,4-Dioxane solution was added. The mixture was stirred at room temperature for 7 hours and then at 4 ° C. overnight. The clear solution at the top was poured out and the sticky solid at the bottom of the flask was dried under vacuum to give the product. LC-MS: m / z = 139 (M + H) ⁺ , RT = 0.44 minutes.

Preparation Example 10-4- (2,2,2-trifluoroethyl) formation of piperidine

Preparation Example 11- (1R, 5S) -3-Azabicyclo [3.1.0] Formation of hexane-1-ol

Preparation Example 12-4- (1H-indole-4-yl) piperidine-1-carboxylate formation of tert-butyl

Preparation Example 13-1,1,1,3,3,3-hexafluoro-2- (piperidine-4-yl) formation of propan-2-ol

Preparation Example 14-4-((3,4-difluorophenyl) sulfonyl) piperidine formation

Preparation Example 15-1- (2,2-difluorocyclopentyl) piperazine formation

Preparation Example 16-4- (trifluoromethyl) azepane

Preparation Example 17-2- (Pyridine-4-yl) -4,5,6,7-Tetrahydrothiazolo [5,4-c] Pyridine

Example 947-953

Examples 947-953 of Table 32 (Table 23) were prepared by coupling the appropriate carboxylic acid with the appropriate amine using specific reaction conditions.

Example 954 Assay for SPR inhibitory activity

Compounds were assayed for SPR inhibitory activity using the TR-FRET (uniform, time-resolved, fluorescence resonance energy transfer) assay according to the procedure described in Haruki et al., Science, 430: 987 (2013). In this assay, terbium-labeled SNAP-hSPR and SSZ (sulfasalazine) -labeled SNAP-EGFP were used as protein pairs. Compounds were screened at different concentrations and IC50 and Kd values were calculated. The SPR inhibitory activity of the compounds is shown in Table 33 (Table 24).

Compounds were assayed for SPR inhibitory activity using the SKN-N-BE (2) cell assay according to the following procedure. SK-N-BE (2) cells were seeded on sterile 96-well plates and _{incubated with a 5% CO 2} feed at 37 ° C. for 12-24 hours. Medium was removed and fresh DMEM / F-12 medium (containing glutamine and Pen / Strep but not FBS) was added. Compounds (at different concentrations) were added to different wells. The plates were then _{incubated with a 5% CO 2} feed at 37 ° C. for 6-48 hours. The plate was then centrifuged and the supernatant was removed. The plate was then optionally washed once with PBS. They were then sealed and stored at -80 ° C or immediately used in the next step. Cells were lysed and BH4 levels were evaluated by LC-MS. The SPR inhibitory activity of the compounds is shown in Table 33 (Table 24).

Compounds were assayed for inhibition of BH4 production using human peripheral blood mononuclear cells (PBMC) according to the following procedure. PBMCs were purchased or isolated from fresh human blood and used as fresh preparations or frozen for later use. The assay system was prepared by pretreating the assay plate overnight with a solution containing anti-human CD3 antibody. Human PBMC were suspended in assay medium and seeded in assay plates at a density of 1 to 4 × 10 ⁵ cells per well. The desired concentration of test compound was added to each well. A solution of human anti-CD28 antibody was also added to each well. Incubate the plate at 37 ° C. and 5% CO ₂ for 12-48 hours. The assay plate was centrifuged at 1 to 3,000 RMP for 5 to 15 minutes and the supernatant was removed. Cells were lysed, sealed and used directly or frozen at 80 ° C. The amount of inhibition of BH4 production was quantified using LC-MS and is shown in Table 33 (Table 24).

Example 955-Behavioral Pharmacology Model

The compounds are standard behavioral pharmacological models for rat pain described in the literature (eg, Latremoriere et al., Neuron, 86: 1393-1406 (2015); Tegeder et al., Nature Medicine, 12: 1269-1277 (2006)). Tested in. Compound Two Nerve Injury Surgery: Preliminary Nerve Injury (SNI, Decosterd et al., Pain, 87: 149-158 (2000)) or Chronic Contraction Injury of the Sciatic Nerve, Injuring Two of the Three Peripheral Branches of the Sciatic Nerve Rats treated with any one of (CCI, Bennett et al., Pain, 33: 87-107 (1988)) were administered by oral gavage. A foot withdrawal threshold for mechanical stimuli with calibrated von Flyfilament was used as a measure of neuropathic pain-like behavior. The effects on pain behavior in these models are shown in Table 34 (Table 25).

The present invention is described in connection with preferred embodiments. However, it should be understood that the present invention is not limited to the disclosed embodiments. Given the description of embodiments of the invention herein, it will be understood that various modifications can be made by those skilled in the art. Such changes are included in the claims below.

Claims (14)

A compound of formula I or I'or a pharmaceutically acceptable salt thereof:

During the ceremony:
The following compounds:

Is the following compound:

Selected from the group consisting of
L is

Is;
n is 0 or 1;
Q is CH, CR ⁶ or N;
Each R ⁶ is C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, halo, benzyl, C _1-5 haloalkylene-OH, C _1-5 alkylene-CN, C. _1-5 Alkoxy, C _1-5 Haloalkoxy, Aryloxy, Heteroaryloxy, CN, OH, -NHR ¹¹ , -NR ¹¹ CO ₂ R ^11a , -SO ₂ R ¹¹ , -SO ₂ NHR ¹¹ , -SOR ¹¹ , -CO ₂ R ¹¹ , -CONHR ¹¹ , aryl, and heteroaryl; and R ¹¹ and R ^11a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, respectively. Selected from the group consisting of -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl.} ,
R ³ and ^{R 4,} together with the nitrogen atom to which they are attached, 3, 4, 5, 6 or 7-membered monocyclic or 6,7,8,9,10,11,12,13 or 14-membered spiro ring, form a fused ring and / or bridged polycyclic Shikiwa; or R ^3, _{H, C 1-5 alkyl, C 3-10 cycloalkyl, C 1-5} haloalkyl, aryl, heteroaryl , And C _1-5 alkylene-G selected from the group
R ⁴ is _{selected from the group consisting of C 1-5} alkyl, C _3-10 cycloalkyl, C _1-5 haloalkyl, aryl, heteroaryl, and C _1-5 alkylene-G; and each G is independent. Te, CN, aryl, heteroaryl, Ru is selected from the group consisting of cycloalkyl, and heterocycloalkyl,
A compound of formula I or I', or a pharmaceutically acceptable salt thereof.

Is,
The compound according to claim 1. L is

The compound according to claim 1. R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 3, 4, 5, 6 or 7-membered ring.
The compound according to any one of claims 1 to 3. The 3, 4, 5, 6 or 7-membered ring is piperidinyl, pyrrolidinyl, azetidinyl, piperazinyl, morpholinyl, thiomorpholinyl, aziridinyl, oxazilidinyl, imidazolidinyl, pyrazolydinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolydinyl, Diazepanyl or diazabicycloheptane,
The compound according to claim 4. A compound of formula I or I'or a pharmaceutically acceptable salt thereof:

During the ceremony:
The following compounds:

Is the following compound:

Selected from the group consisting of
L is

Is;
n is 0 or 1;
Q is CH, CR ⁶ or N;
Each R ⁶ is C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, halo, benzyl, C _1-5 haloalkylene-OH, C _1-5 alkylene-CN, C. _1-5 Alkoxy, C _1-5 Haloalkoxy, Aryloxy, Heteroaryloxy, CN, OH, -NHR ¹¹ , -NR ¹¹ CO ₂ R ^11a , -SO ₂ R ¹¹ , -SO ₂ NHR ¹¹ , -SOR ¹¹ , -CO ₂ R ¹¹ , -CONHR ¹¹ , aryl, and heteroaryl;
R ¹¹ and R ^11a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, respectively. , -C _0-5 alkylene-aryl, and -C _0-5 alkylene-heteroaryl.
R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are 3, 4, 5, 6 or 7-membered monocycles or 6, 7, 8, 9, 10, 11, 12, 13 or Forming a 14-membered spiro ring, fused ring and / or crosslinked polycyclic ring, or independently of each, halo, C _1-5 alkyl, C _1-5 haloalkyl, C _1-5 alkoxy, aryloxy, hetero One or two substituents selected from the group consisting of aryloxy, CN, OH, -SO ₂ R ¹⁰ , -CO ₂ R ¹⁰ , -CONHR ¹⁰ , C _{3-5 cycloalkyl, oxo, aryl and heteroaryl.} 3, 4, 5, 6 or 7-membered monocyclic or 6,7,8,9,10,11,12,13 or 14-membered spiro ring, fused ring and / or crosslinked polycyclic ring substituted with And R ¹⁰ is selected from the group consisting of H, C _1-5 alkyl, -C _0-5 alkylene-aryl, and -C _{0-5 alkylene-heteroaryl, or}

Is;
m is 0, 1, 2 or 3;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _{1-5, respectively.} Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^8, -CONHR ^8, aryl, and heteroaryl, or two ^{R 7} together with the carbon atoms to which they are attached, 4, 5, 6, 7 or 8 Forming a membered cycloalkyl, 3, 4, 5, 6, 7 or 8-membered heterocycloalkyl, aryl, or 5- or 6-membered heteroaryl ring; and R ⁸ and R ^8a , respectively, independently. H, C _1-5 alkyl, C _1-5 haloalkyl, -C _0-5 alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl and -C _0-5 alkylene - is selected from the group consisting of heteroaryl; or one of R ⁷ and R ^9, form a heterocyclic or heteroaryl ring together with the atoms to which they are attached a 5 or 6-membered To do
A compound of formula I or I' , or a pharmaceutically acceptable salt thereof .

Is;
R ⁷ and R ⁹ are independently halo, C _1-5 alkyl, C _3-5 cycloalkyl, heterocycloalkyl, C _1-5 haloalkyl, C _1-5 haloalkylene-OH, C _1-5. Alkylene-CN, C _1-5 alkoxy, C _1-5 haloalkoxy, aryloxy, heteroaryloxy, CN, OH, -NHR ⁸ , -NR ⁸ CO ₂ R ^8a , -SO ₂ R ⁸ , -CO ₂ R ^{Selected from the group consisting of 8} , -CONHR ⁸ , aryl, and heteroaryl; and R ⁸ and R ^8a are independently H, C _1-5 alkyl, C _1-5 haloalkyl, -C _{0-5, respectively.} Selected from the group consisting of alkylene-C _3-6 cycloalkyl, -C _0-5 alkylene-heterocycloalkyl, -C _0-5 alkylene-aryl and -C _{0-5 alkylene-heteroaryl.}
The compound according to claim 6. R ⁷ or R ⁹ is _{selected from the group consisting of C 3-5} cycloalkyl, heterocycloalkyl, aryloxy, heteroaryloxy, aryl and heteroaryl.
The compound according to claim 6 or 7. R ⁷ is oxazolyl or pyridinyl, each optionally substituted with CN or F,
The compound according to any one of claims 6 to 8. R ⁹ is C _3-5 cycloalkyl,
The compound according to any one of claims 6 to 9. R ⁹ is cyclopropyl or cyclobutyl, each optionally substituted with 1, 2, 3 or 4 F atoms.
The compound according to any one of claims 6 to 10.

Is,
The compound according to claim 8. At least one R ⁷ or R ⁹ is F, CF ₃ , CH ₃ , CH ₂ CH ₃ , -CH ₂ CF ₃ , cyclopropyl, 1-cyano-cyclopropyl, CN, -C (CH ₃ ) ₂ CN, -CH (CN) CH ₂ CH ₃ , 3, 3-difluoropyrrolidin, -OH, -OCH ₃ , OCH ₂ CH ₃ , -OCH ₂ CF ₃ , -C (OH) (CF ₃ ) ₂ , -C (OH) ) CH ₃ CF ₃ , -CO ₂ C (CH ₃ ) ₃ , -CONHC (CH ₃ ) ₃ , -N (CH ₃ ) CO ₂ C (CH ₃ ) ₃ , Phenoxy, Phenylsulfonyl 3,4-difluorobenzene sulfonyl, phenyl, fluorophenyl, difluorophenyl, cyanophenyl, indolyl, or difluoromethoxy pyrrolidinylmethyl or benzothiazolyl, or two R ⁷ are taken together with the carbon atoms to which they are attached, a fused benzene ring Form,
The compound according to claim 6 or 12. To any one of請Motomeko 1-13 comprising a compound according antiinflammatory agents or immune cell modulation agents for the treatment of acute or chronic pain.